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Iatrogenic Cushing Syndrome Clinical Presentation

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

History

Patients with Cushing syndrome may experience weight gain, especially in the face, supraclavicular region, upper back, and torso. Frequently, patients notice changes in their skin, including purple stretch marks, easy bruising, and other signs of skin thinning. Because of progressive proximal muscle weakness, patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms.

Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in women related to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing hormone-releasing hormone (LHRH) pulse generation. In men, inhibition of LHRH and FSH/LH function may lead to decreased libido and impotence.

Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop. New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur.

When seeing a patient with symptoms suggestive of Cushing syndrome, inquire about history of drug use, duration, and dosing, including over the counter drugs and herbal preparations. A good and detailed history can provide very useful information to exclude drug-related Cushing syndrome before proceeding with further diagnostic tests.

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Physical

Obesity

Patients may have increased adipose tissue in the face (moon facies), upper back at the base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).

Central obesity with increased adipose tissue in the mediastinum and peritoneum; increased waist-to-hip ratio greater than 1 in men and 0.8 in women. Increased visceral fat is easily observed and measured with CT scan of the abdomen.

Skin

Facial plethora may be present, especially over the cheeks. Violaceous striae, often wider than 0.5 cm, are observed most commonly over the abdomen, buttocks, lower back, upper thighs, upper arms, and breasts. Ecchymoses may be present. Patients may have telangiectasias and purpura.

Cutaneous atrophy with exposure of subcutaneous vasculature tissue and tenting of skin may be evident. Glucocorticoid excess may cause increased lanugo facial hair. If glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocortical carcinomas, hirsutism and male pattern balding may be present in women. Steroid acne, consisting of papular or pustular lesions over the face, chest, and back, may be present. Acanthosis nigricans, which is associated with insulin resistance and hyperinsulinism, may be present. The most common sites are axilla and areas of frequent rubbing, such as over elbows, around the neck, and under the breasts.

Gastroenterologic

Peptic ulceration may occur with or without symptoms. Particularly at risk are patients given high doses of glucocorticoids.

Skeletal/muscular

Proximal muscle weakness may be evident. Osteoporosis may lead to incident fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip is also possible from glucocorticoid excess.

Adrenal crisis

Patients with cushingoid features may present to the emergency department in adrenal crisis. Adrenal crisis may occur in patients on steroids who stop taking their glucocorticoids or neglect to increase their steroids during an acute illness. See Glucocorticoid Therapy and Cushing Syndrome.

Physical findings that occur in a patient in adrenal crisis include hypotension, abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia, and metabolic acidosis.

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Causes

The most common cause of iatrogenic, or drug-related, Cushing syndrome is glucocorticoids. Glucocorticoid use via different routes, including injected, oral, epidural,[6] inhaled,[7] nasal,[8] or topical,[9] if prolonged and potent enough, can cause Cushing syndrome.

The effect of drug interactions should be taken into consideration, especially with agents that can inhibit cytochrome P450. Via the pathway of cytochrome P450, glucocorticoid is metabolized in the liver by the CYP3A4 isoenzyme into inactive metabolites. Therefore, drugs that inhibit cytochrome P450 activity can lead to prolonged action of glucocorticoids. Cases of iatrogenic Cushing syndrome due to interaction of glucocorticoid products and cytochrome P450 inhibitors such as itraconazole,[10] ritonavir,[11, 12] and antidepressants[13] have been reported.

Duman and Fulco reported on a case of probable drug-induced Cushing syndrome, followed by adrenal insufficiency, caused by the concomitant use of the oral voriconazole (an antifungal, CYP3A4 inhibitor) with intranasal mometasone and inhaled fluticasone.[14]

Epperla and McKiernan reported on a case of iatrogenic Cushing syndrome, severe osteoporosis, and adrenal insufficiency, resulting from the concomitant use of ritonavir and inhaled fluticasone in a patient with human immunodeficiency virus (HIV).[15]

Patients with diseases that respond to steroid therapy are especially likely to receive steroids and, thus, develop Cushing syndrome. Such disorders include a wide variety of rheumatologic, pulmonary, neurological, andrenal diseases. Patients who have undergone organ transplants are also at risk for developing Cushing syndrome due to exogenous steroids required as part of graft antirejection regimens.

Megestrol acetate (a progestin with intrinsic glucocorticoid activity)[16] and herbal preparations[17, 18] have also been known to cause Cushing syndrome.

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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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