Iatrogenic Cushing Syndrome

Practice Essentials

Cushing syndrome, first described by Harvey in 1912, refers to signs and symptoms caused by excess free plasma glucocorticoids. Excess glucocorticoids can arise 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 focus on iatrogenic Cushing syndrome.^[1]

The diagnosis of Cushing syndrome requires demonstration of an inappropriately high level of cortisol in the serum or urine. Drugs that have been reported to result in hypercortisolism are glucocorticoids, megestrol acetate, and herbal preparations that contain glucocorticoids.

Signs and symptoms of Cushing syndrome

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Physical findings in Cushing syndrome.

Patients may have increased adipose tissue in the face (moon facies), upper back at the base of the 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.

With regard to Cushing syndrome’s effects on the 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
• Hirsutism and male pattern balding may be present in women if glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocortical carcinomas
• 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

Gastroenterologic and skeletal/muscular signs and symptoms can include the following:

• Peptic ulceration may occur with or without symptoms
• 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 possible from glucocorticoid excess

The major complications associated with Cushing syndrome are cardiovascular disease, thromboembolic events, susceptibility to opportunistic infections, neuropsychiatric complications, and gonadal dysfunction.^[2]

Workup in Cushing syndrome

As mentioned, the diagnosis of Cushing syndrome requires demonstration of an inappropriately high level of cortisol in the serum or urine. The following tests have been recommended as screening tests for Cushing syndrome^{[3, 4]} :

• Midnight serum or salivary cortisol^{[5, 6, 7]}
• 24-hour urine free cortisol
• 1-mg overnight dexamethasone suppression test
• 48-hour, low-dose dexamethasone suppression test (Liddle test)

An adrenocorticotropic hormone (ACTH) level obtained at the same time as the cortisol level can be helpful in identifying the etiology of Cushing syndrome.

Management of Cushing syndrome

The treatment for exogenous Cushing syndrome is gradual withdrawal of the causative drug, with the aim of discontinuing the causative drug if possible. An individual with hypothalamic-pituitary-adrenal (HPA)–axis suppression cannot increase steroid production appropriately during a medical illness or other stress and should receive stress-dose steroids to avoid adrenal crisis.^[8]

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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

Untreated Cushing syndrome is associated with a 5-year mortality rate of 50%. This reflects a four- to five-fold increase in mortality over the general population and is attributable to factors such as cardiovascular complications, thromboembolic events, opportunistic infections, and suicide.^{[9, 10]}

Exogenous steroids suppress the hypothalamic-pituitary-adrenal (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 abruptly or are not increased appropriately during an acute illness.

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Pathophysiology

Glucocorticoids’ bioavailability is between 60% and 100%. More than 90% of the circulating glucocorticoid binds to corticosteroid-binding globulin (CBG), while the unbound free hormone in the circulation binds to the glucocorticoid receptor (GR). Except for prednisolone, all synthetic glucocorticoids have a relatively low affinity for 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.^[11]

Structural differences between glucocorticoid compounds result in different bioavailability, duration, onset of action, potency, and metabolic profiles of each product. Down-regulation of nuclear factor-kappa B activation,^[12]  changes in the enzyme adenosine monophosphate-activated protein kinase's activity,^[13] and modulation of activator protein 1 (Fos/Jun)^[14] are some of the important pathways that have been described. More research needs to be conducted to improve understanding of 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.^[15]

Table 1. Glucocorticoid Equivalencies^[16]

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See Table

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Patient Education

Patients and their families need to be educated on the expected quality of life with Cushing syndrome and on complications of the disease, such as life-threatening adrenal crisis. Patient education of sick-day rules is crucial for individuals' safety and well-being. Patients must also be educated about the importance of maintaining a healthy lifestyle, including regular physical activity and adequate rest.

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History

Patients with Cushing syndrome present with a wide variety of subtle, non-specific features, often resulting in a delay in their diagnosis. They may experience weight gain, especially in the face, supraclavicular region, upper back, and torso. Patients frequently notice skin changes, 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 in relation to inhibition of pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, inhibition of LH-releasing hormone (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.

Neuropsychiatric problems such as depression, cognitive dysfunction, emotional lability, and increased suicidality may develop. These symptoms can manifest a few days after glucocorticoid treatment begins and resolve a few days after such therapy ends.^[17]

A correlation was observed between glucocorticoid dosage levels and various clinical manifestations, with certain adverse effects becoming more pronounced beyond a specific threshold of daily glucocorticoid intake. For instance, epistaxis and weight gain were noted at doses exceeding 5 mg of prednisone equivalent per day, while depression, glaucoma, and high blood pressure were notably prevalent with doses surpassing 7.5 mg per day. Eye cataracts were detected at a very low threshold of less than 5 mg per day.^[18]

When encountering a patient with symptoms suggestive of Cushing syndrome, a clinician should always inquire about the individual's history of drug use, including over-the-counter medications and herbal preparations. A detailed history can provide 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 the 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 occur. 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 as well as kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis of the hip is also possible from glucocorticoid excess.

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Causes

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 the graft antirejection regimens. Glucocorticoid use via different routes, including injected, oral, epidural,^[19] inhaled,^[20] nasal,^[21] or topical,^[22] if prolonged and potent enough, may cause Cushing syndrome.

Megestrol acetate (a progestin with intrinsic glucocorticoid activity)^[23]  and herbal preparations^{[24, 25]}  have also been known to 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,^[26] ritonavir,^{[27, 28]} and antidepressants^[29] have been reported.

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Complications

Cushing syndrome, whether exogenous or endogenous, is associated with a vast array of complications. Some of these complications may persist even after the removal of the inciting factor, making prompt diagnosis and treatment of utmost importance.^[30] Hypercortisolism has been found to be associated with hypertension, hyperlipidemia, insulin resistance, hypercoagulability, hypogonadism, osteoporosis, avascular necrosis of the hip, peptic ulcer disease, and nephrolithiasis.^{[31, 2]}

The neuropsychiatric complications seen in Cushing syndrome are depression, anxiety, posttraumatic stress disorder, mania, bipolar disorder, psychosis, and cognitive impairment.^[32]

Individuals with Cushing syndrome also exhibit cellular immunosuppression, making them more susceptible to infection.^[33]

In addition, patients with Cushing syndrome are at high risk for 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 who is 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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Laboratory Studies

Before performing chemical testing, a detailed drug history must be elicited. In some cases of unreported exogenous steroid use, biochemical tests will need to be performed to confirm a diagnosis. The diagnosis of Cushing syndrome requires the demonstration of an inappropriately high level of cortisol in the serum or urine. The levels should be measured at times when cortisol concentrations, according to their physiologic circadian rhythm, are expected to be suppressed.

This concept gives rise to the following tests, which have been recommended as screening tests for Cushing syndrome:^{[3, 4]}

• Midnight serum or salivary cortisol (at least two measurements)^{[5, 6, 7]}
• 24-hour urine free cortisol
• 1-mg overnight dexamethasone suppression test
• 48-hour, low-dose dexamethasone suppression test (Liddle test)

Patients with at least one abnormal test or a high pre-test probability of Cushing syndrome should be referred to an endocrinologist for further evaluation.^[37]

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Other Tests

A study by Álvarez-Hernández et al indicated that the clinical severity index of Cushing syndrome, developed by Sonino et al, while useful in endogenous Cushing syndrome, can also effectively be employed in patients with the iatrogenic form of the condition. Once the definitions of the subjective clinical variables had been standardized, the investigators found that the index adequately correlated with clinical manifestations associated with chronic glucocorticoid use.^[38]

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Medical Care

The appropriate treatment for exogenous Cushing syndrome is gradual withdrawal of the causative drug, with the aim of discontinuing this agent if possible. This can be a lengthy process that may take several months to a year, depending on the duration and dosages of the glucocorticoids used. It is important to remember that during this process, an individual with HPA-axis suppression cannot increase steroid production appropriately during a medical illness or other stress and should receive stress-dose steroids to avoid adrenal crisis.^[8]

See Glucocorticoid Therapy and Cushing Syndrome.

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