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.
New-onset or worsening of hypertension and diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and osteoporotic fractures may occur.
Psychological problems such as depression, cognitive dysfunction, and emotional lability may develop. Neuropsychological symptoms and cognitive impairment can manifest a few days after glucocorticoid treatment begins and resolve a few days after such therapy ends. Treatment duration and dose are positively correlated with the risk of these side effects. The association of glucocorticoids with severe neuropsychiatric symptoms, including confusion and suicide attempts, also has been found to be dose dependent. It has been reported that memory and executive function can be impaired by glucocorticoid treatment as well. Evidence indicates that glucocorticoid administration particularly impacts the consolidation, as opposed to the acquisition, of memories, with patients retaining immediate recall abilities. [14]
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.
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 is characterized by increased adipose tissue in the mediastinum and peritoneum and an increased waist-to-hip ratio of greater than 1 in men and higher than 0.8 in women. Increased visceral fat is easily observed and measured with computed tomography (CT) scanning 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.
Causes
The most common cause of iatrogenic, or drug-related, Cushing syndrome is glucocorticoids. Glucocorticoid use via different routes, including injected, oral, epidural, [15] inhaled, [16] nasal, [17] or topical, [18] 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, [19] ritonavir, [20, 21] and antidepressants [22] 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. [23]
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). [24]
Joshi and Maresh reported on two infants with nasal obstruction who developed Cushing syndrome after being treated with intranasal dexamethasone drops. [25]
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, neurologic, and renal 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. A case study by Yeoh described the development of Cushing syndrome following the administration of ritonavir for the treatment of hepatitis C and oral budesonide for autoimmune hepatitis. [26]
Megestrol acetate (a progestin with intrinsic glucocorticoid activity) [27] and herbal preparations [28, 29] have also been known to cause Cushing syndrome.
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Physical findings in Cushing syndrome.
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Diagnosis of Cushing syndrome.
Tables
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 |
… |
