Iatrogenic Cushing Syndrome
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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 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. [1]
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.
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.
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.
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.
Glucocorticoids’ 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. [2]
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, [3] changes in the enzyme adenosine monophosphate-activated protein kinase activity, [4] and modulation of activator protein 1 (Fos/Jun) [5] 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.
A study by Serfling et al suggested that weight gain in iatrogenic Cushing syndrome may be related to a glucocorticoid-stimulated rise in the amygdala and insula’s blood oxygen level–dependent (BOLD) response to approach-associated food stimuli. Thus, glucocorticoids may increase the anticipated reward value of food, leading to greater food consumption. [6]
Table 1. Glucocorticoid Equivalencies [7] (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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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
…
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.
Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, Sidney Kimmel 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
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: Received salary from Medscape for employment. for: Medscape.
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.
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
Iatrogenic Cushing Syndrome
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