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Iatrogenic Cushing Syndrome

  • Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 20, 2016
 

Background

Cushing syndrome, first described by Harvey in 1912, refers to signs and symptoms caused by excess free plasma glucocorticoids. Excess glucocorticoids can be from increased endogenous production or prolonged exposure to exogenous use of glucocorticoid products. While endogenous Cushing’s syndrome is a rare disease, iatrogenic (drug-related or exogenous) Cushing syndrome from glucocorticoid products is commonly seen in clinical practice. This article will focuses on iatrogenic, or drug-related, Cushing syndrome.

Drugs that have been reported to result in hypercortisolism are glucocorticoids, megestrol acetate, and herbal preparations that contain 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. Physical findings in Cushing syndrome.

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

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Frequency

Most cases of Cushing syndrome are due to exogenous glucocorticoids. Prevalence of exogenous Cushing syndrome depends on the frequency and spectrum of medical conditions requiring glucocorticoid treatment in a given population. Considerable variation in this frequency is observed in populations of different cultural and ethnic backgrounds.

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Mortality/Morbidity

Morbidity and mortality associated with Cushing syndrome are related primarily to the effects of excess glucocorticoids.

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.

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Pathophysiology

Glucocorticoids’s bioavailability is between 60% and 100%. More than 90% of the circulating glucocorticoid binds to corticosteroid binding globulin (CBG).The unbound free hormone in the circulation binds to the glucocorticoid receptor (GR). GR consists of a carboxy terminal ligand binding domain, a DNA binding domain and an N terminal domain. Except for prednisolone, which has an affinity for CBG that is about half of cortisol. Other synthetic glucocorticoids, in comparison to cortisol, have much less affinity to CBG.

Binding of the glucocorticoid to GR results in several intracellular processes of gene transcription and translation that ultimately lead to several actions of glucocorticoids on tissues. Some glucocorticoids can have cross activity with mineralocorticoid receptor (MR) due to significant homology between GR and MR.[1]

Structural differences between glucocorticoid compounds result in different bioavailability, duration, onset of action, potency and metabolic profiles of each product. Downregulation of the nuclear factor-kappa B activation,[2] changes in the enzyme adenosine monophosphate-activated protein kinase activity,[3] and modulation of activator protein 1 (Fos/Jun)[4] are some of the important pathways that have been described. More research still needs to be conducted to fully understand the underlying signaling pathways and glucocorticoid tissue-specific responses.

Table 1. Glucocorticoid Equivalencies[5] (Open Table in a new window)

Type Drug Dose Relative Glucocorticoid Potency Relative Mineralocorticoid Potency Plasma Half-Life



(mg)



Biologic Half-Life



(h)



Short-acting Cortisol 20 1.0 2 90 8-12
Hydrocortisone 25 0.8 2 80-118 8-12
Intermediate-acting Prednisone 5 4 1 60 18-36
Prednisolone 5 4 1 115-200 18-36
Triamcinolone 4 5 0 30 18-36
Methylprednisolone 4 5 0 180 18-36
Long-acting Dexamethasone 0.5 25-50 0 200 36-54
Betamethasone 0.6 25-50 0 300 36-54
Mineralocorticoid Aldosterone 0.3 0 300 15-20 8-12
Fludrocortisone 2 15 150 200 18-36
Desoxycorticosterone acetate 0 0 20 70
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Contributor Information and Disclosures
Author

Ha Cam Thuy Nguyen, MD Fellow, Department of Endocrinology, University of Pittsburgh Medical Center

Ha Cam Thuy Nguyen, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Medical Association, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Catherine Anastasopoulou, MD, PhD, FACE Assistant Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Attending Endocrinologist, Department of Medicine, Albert Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society, National Osteoporosis Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

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.

Disclosure: Nothing to disclose.

Susanna L Dipp, MD Fellow, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School

Disclosure: Nothing to disclose

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

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Physical findings in Cushing syndrome.
Diagnosis of Cushing syndrome.
Table 1. Glucocorticoid Equivalencies [5]
Type Drug Dose Relative Glucocorticoid Potency Relative Mineralocorticoid Potency Plasma Half-Life



(mg)



Biologic Half-Life



(h)



Short-acting Cortisol 20 1.0 2 90 8-12
Hydrocortisone 25 0.8 2 80-118 8-12
Intermediate-acting Prednisone 5 4 1 60 18-36
Prednisolone 5 4 1 115-200 18-36
Triamcinolone 4 5 0 30 18-36
Methylprednisolone 4 5 0 180 18-36
Long-acting Dexamethasone 0.5 25-50 0 200 36-54
Betamethasone 0.6 25-50 0 300 36-54
Mineralocorticoid Aldosterone 0.3 0 300 15-20 8-12
Fludrocortisone 2 15 150 200 18-36
Desoxycorticosterone acetate 0 0 20 70
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