eMedicine Specialties > Endocrinology > Adrenal Gland

Cushing Syndrome

Author: Gail K Adler, MD, PhD, FAHA, Assistant Professor, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School
Contributor Information and Disclosures

Updated: Oct 1, 2009

Introduction

Background

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids.

Individuals with Cushing syndrome can develop moon facies, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae. (See image below and Image 1.)

In an emergency situation, remembering that the most common cause of Cushing syndrome is the use of exogenous glucocorticoids is important. Exogenous steroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can last for as long as a year after exogenous steroid administration has ended.

An individual with HPA-axis suppression cannot increase steroid production appropriately during a medical illness or other stress and would need to receive stress doses of steroids to avoid adrenal crisis. Thus, in an emergency, the potential for relative adrenal insufficiency should be considered in any patient with Cushing syndrome.

Pathophysiology

Excess levels of either exogenously administered glucocorticoids or endogenous overproduction of cortisol causes Cushing syndrome. Endogenous glucocorticoid overproduction or hypercortisolism that is independent of adrenocorticotropic hormone (ACTH) is usually due to a primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing syndrome.

ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. They usually are due to an anterior pituitary tumor, that is, classic Cushing disease (80%). Nonpituitary ectopic sources of ACTH, such as an oat cell carcinoma, small-cell lung carcinoma, or carcinoid tumor, cause the balance of ACTH-dependent disease. Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion comprise a very rare group of cases of Cushing syndrome.¹

Frequency

United States

Most cases of Cushing syndrome are due to exogenous glucocorticoids. The annual incidence of endogenous Cushing syndrome has been estimated at 13 cases per million individuals. Of these cases, approximately 70% are due to Cushing disease, that is, a pituitary ACTH-producing tumor; 15% to ectopic ACTH; and 15% to a primary adrenal tumor.

Mortality/Morbidity

Morbidity and mortality associated with Cushing syndrome are related primarily to the effects of excess glucocorticoids. However, a large primary pituitary tumor may cause panhypopituitarism and visual loss. 

• In addition, the rare adrenocortical carcinomas are associated with a 5-year survival rate of 30% or less.
• 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.
• Similarly, lack of cortisol leading to an adrenal crisis may occur in patients with endogenous Cushing syndrome who have undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.

Sex

• The female-to-male incidence ratio is approximately 5:1 for Cushing syndrome due to an adrenal or pituitary tumor.
• Ectopic ACTH production is more frequent in men than in women because of the increased incidence of lung tumors in this population.

Age

• The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma is in persons aged 25-40 years.
• Ectopic ACTH production due to lung cancer occurs later in life.

Clinical

History

• Patients with Cushing syndrome may complain of 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 due 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.
• Patients with an ACTH-producing pituitary tumor (Cushing disease) may develop headaches, polyuria and nocturia, visual problems, or galactorrhea.
• If sufficient mass effect from the tumor is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyperprolactinemia or hypoprolactinemia, and hypogonadism may develop.
• Rapid onset of symptoms of glucocorticoid excess in conjunction with virilization in women or feminization in men suggests an adrenal carcinoma as the underlying cause of the Cushing syndrome.

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; and, upon CT scan of the abdomen, increased visceral fat is evident.
• 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.
• Cardiovascular and renal
  • Hypertension and possibly edema may be present due to cortisol activation of the mineralocorticoid receptor leading to sodium and water retention.
• Gastroenterologic
  • Peptic ulceration may occur with or without symptoms. Particularly at risk are patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).
• Endocrine
  • Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk, leading to elevated prolactin levels.
  • Signs of hypothyroidism, such as slow reflex relaxation, may occur from an anterior pituitary tumor whose size interferes with proper thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) function. Similarly, other pituitary function may be interrupted.
  • Low testosterone levels in men may lead to decreased testicular volume from inhibition of LHRH and LH/FSH function.
• 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.
• Neuropsychological
  • Patients may experience emotional liability, fatigue, and depression.
  • Visual-field defects, often bitemporal, and blurred vision may occur in individuals with large ACTH-producing pituitary tumors that impinge on the optic chiasma.
• 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. It also may occur in patients who have recently undergone resection of an ACTH-producing or cortisol-producing tumor or who are taking adrenal steroid inhibitors.
  • 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

• Exogenous steroid administration
  • Administration of exogenous steroids may lead to the development of Cushing syndrome.
  • Symptoms of glucocorticoid excess generally occur with the administration of oral steroids; however, occasionally injections of steroids into joints and the use of steroid inhalers can cause Cushing syndrome.
  • 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, and nephrologic 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 medication regimens.
• Endogenous glucocorticoid overproduction
  • ACTH-producing pituitary adenoma
    • Pituitary adenomas that secrete ACTH are derived from corticotrophs in the anterior pituitary.
    • ACTH secreted by corticotrophs is released into the circulation and acts on the adrenal cortex to produce hyperplasia and stimulate the secretion of adrenal steroids.
    • These adenomas, if large, can result in loss of production of other anterior pituitary hormones (TSH, FSH, LH, growth hormone, and prolactin) and the posterior pituitary hormone vasopressin.
    • Pituitary tumors can also compress the hypophyseal stalk leading to hyperprolactinemia from loss of dopamine inhibition.
    • Nelson syndrome is caused by a large ACTH-secreting pituitary tumor; it is often locally invasive, difficult to cure, and associated with hyperpigmentation. In patients who undergo adrenalectomy without pituitary irradiation, the incidence of Nelson syndrome is about 20-25%.
  • Large pituitary adenomas may press on the optic chiasm, causing visual-field deficiencies that often present as bitemporal field cuts.
  • Primary adrenal lesions
    • Overproduction of glucocorticoids may be due to an adrenal adenoma, adrenal carcinoma, or macronodular or micronodular adrenal hyperplasia. The zona fasciculata and zona reticularis layers of the adrenal cortex normally produce glucocorticoids and androgens. Glucocorticoid-secreting tumors are derived from these cells and, thus, may secrete both glucocorticoids and androgens.
    • In general, excess androgen secretion is suggestive of an adrenal carcinoma rather than an adrenal adenoma. These glucocorticoid-producing tumors generally do not secrete aldosterone, which is produced in the zona glomerulosa layer of the adrenal cortex.
    • The Carney complex is a familial form of micronodular hyperplasia of the adrenal gland. It is an autosomal dominant disorder and ACTH independent cause of Cushing syndrome. Pigmented skin lesions and mesenchymal and endocrine tumors characterize the disorder. Cushing syndrome may be overt, subclinical, cyclical, or periodic.
    • McCune-Albright syndrome is a rare cause of precocious puberty. It is associated with hyperfunction of the adrenal glands that may lead to Cushing syndrome.
• Ectopic ACTH is sometimes secreted by oat cell or small-cell lung tumors or by carcinoid tumors.

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