Iatrogenic Cushing Syndrome 

Updated: Aug 26, 2020
Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

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.

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.

Signs and symptoms of Cushing syndrome

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.

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

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.

Workup in Cushing syndrome

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:[2, 3]

  • Midnight serum or salivary cortisol [4, 5, 6]
  • 24-hour urine free cortisol
  • 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.[7]

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.

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 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 or not increased during an acute illness.

Pathophysiology

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.[8]

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,[9] changes in the enzyme adenosine monophosphate-activated protein kinase activity,[10] and modulation of activator protein 1 (Fos/Jun)[11] 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.[12]

Table 1. Glucocorticoid Equivalencies [13] (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

 

Presentation

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.

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,[14] inhaled,[15] nasal,[16] or topical,[17] 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,[18] ritonavir,[19, 20] and antidepressants[21] 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.[22]

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).[23]

Joshi and Maresh reported on two infants with nasal obstruction who developed Cushing syndrome after being treated with intranasal dexamethasone drops.[24]

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.[25]

Megestrol acetate (a progestin with intrinsic glucocorticoid activity)[26] and herbal preparations[27, 28] have also been known to cause Cushing syndrome.

 

DDx

Diagnostic Considerations

Iatrogenic, or drug-related Cushing syndrome, should be differentiated from physiologic hypercortisolism (pseudo-Cushing syndrome) and endogenous Cushing syndrome.

Differentiation of Cushing syndrome from pseudo–Cushing syndrome can sometimes be a challenge. A pseudo-Cushing state is defined as having some of the clinical features and biochemical evidence of Cushing syndrome. However, resolution of the primary condition results in disappearance of the cushingoid features and biochemical abnormalities.[29, 30]

In patients who chronically abuse alcohol, clinical and biochemical findings suggestive of Cushing syndrome are often encountered. Discontinuation of alcohol causes disappearance of these abnormalities, and, therefore, this syndrome is often specifically referred to as alcohol-induced pseudo-Cushing syndrome.

Patients with depression often have perturbation of the HPA axis, with abnormal cortisol hypersecretion. These patients rarely develop clinical Cushing syndrome. Because excess glucocorticoids can lead to emotional liability and depression, distinguishing between depression and mild Cushing syndrome is often a diagnostic challenge.

Obesity is also a cause of pseudo-Cushing state.[31]

Differential Diagnoses

 

Workup

Laboratory Studies

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 when cortisol, according to its physiologic circadian rhythm, is supposed to be suppressed, meaning at midnight or when a patient is given exogenous glucocorticoids.

This concept gives rise to the following tests, which have been recommended as screening tests for Cushing syndrome:[2, 3]

  • Midnight serum or salivary cortisol[4, 5, 6]

  • 24-hour urine free cortisol

  • 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.

Diagnosis of Cushing syndrome. Diagnosis of Cushing syndrome.

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 (specifically, in this report, those who had undergone at least 4 weeks of glucocorticoid treatment for rheumatologic disease). Once the definitions of subjective clinical variables had been standardized, the investigators found that the index adequately correlated with clinical manifestations associated with chronic glucocorticoid use.[32]

 

Treatment

Medical Care

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 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.[7]

See Glucocorticoid Therapy and Cushing Syndrome.

 

Follow-up

Complications

Complications of Cushing syndrome include the following:

  • Osteoporosis

  • Increased susceptibility to infections

  • Hirsutism

  • Diabetes mellitus

  • Hypertension

  • Risk for adrenal crisis

Patients with Cushing syndrome due to exogenous steroid use are at risk for having an adrenal crisis if they do not receive stress dose steroids during acute illnesses. Untreated adrenal crises can lead to death.

High levels of exogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel.

Patient Education

Patients should be educated about adrenal crisis, sick day rules within the following year after exogenous glucocorticoids is stopped, and medical bracelet alert.

Instruction on specific medication use is indicated.

 

Questions & Answers