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, as shown in the image below.
Physical findings in Cushing syndrome. Individuals often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes mellitus, and impaired immune function may occur.
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 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]
Epidemiology
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.
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| States of Increased HPA Activity | States of Decreased HPA Activity |
| Chronic stress[9] Melancholic depression Anorexia nervosa Obsessive-compulsive disorder Panic disorder Excessive exercise Chronic active alcoholism Alcohol and nicotine withdrawal Diabetes mellitus Central obesity Sexual abuse Hyperthyroidism Premenstrual tension syndrome Cushing syndrome Pregnancy | Adrenal insufficiency Atypical/seasonal depression Chronic fatigue syndrome Fibromyalgia Hypothyroidism Nicotine withdrawal Post glucocorticoid therapy Post-Cushing syndrome Postpartum period Post-chronic stress[9] Rheumatoid arthritis |

