Endogenous Cushing Syndrome

Updated: May 09, 2017
  • Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Overview

Background

Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids. Exogenous use of glucocorticoids should always be considered and excluded in the etiology of Cushing syndrome. This article focuses on endogenous Cushing syndrome. Endogenous glucocorticoid overproduction, or hypercortisolism, can be dependent on or independent of adrenocorticotropic hormone (ACTH).

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 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.

Also see Glucocorticoid Therapy and Cushing Syndrome and Iatrogenic Cushing Syndrome.

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Pathophysiology

Endogenous glucocorticoid overproduction or hypercortisolism that is independent of ACTH is usually due to a primary adrenocortical neoplasm (most commonly an adenoma and rarely a carcinoma). Bilateral micronodular hyperplasia (primary pigmented nodular adrenocortical disease) and macronodular hyperplasia are rare causes of Cushing syndrome.

Ectopic cortisol secretion from a case of ovarian carcinoma has been reported as a cause of ACTH-independent Cushing syndrome. [1]

ACTH level in ACTH-independent Cushing syndrome is low due to the negative feedback to pituitary corticotroph cells from a high level of serum cortisol. ACTH-dependent Cushing syndrome is characterized by elevated ACTH levels. Elevated ACTH levels are usually due to an anterior pituitary tumor, which is classic Cushing disease (60-70%). Nonpituitary ectopic sources of ACTH, such as small-cell lung carcinoma (oat cell carcinoma), carcinoid tumor, medullary thyroid carcinoma, or other neuroendocrine tumors can result in high ACTH levels and sequentially hypercortisolism.

Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion comprises a very rare group of cases of Cushing syndrome. [2]

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Etiology

The following conditions may cause endogenous glucocorticoid overproduction:

ACTH-independent Cushing syndrome

  • 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 do not usually 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 this disorder. Cushing syndrome may be overt, subclinical, cyclical, or periodic.
    • Primary bilateral macronodular adrenal hyperplasia is uncommon and characterized by multiple nonpigmented nodules that are greater than 10 mm in diameter and enlarged adrenal glands. The exact etiology of this condition is not quite clear, however, genetic mutations, paracrine ACTH secretion, and aberrant hormone receptors have been reported to play a role in its pathogenesis.
    • 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. [3]
  • Ectopic cortisol secretion from a case of ovarian carcinoma has been reported as a cause of ACTH independent Cushing syndrome. [1]

ACTH-dependent Cushing syndrome

  • ACTH-producing pituitary adenoma
    • Pituitary adenomas that secrete ACTH are derived from corticotroph cells in the anterior pituitary.
    • ACTH secreted by corticotroph cells 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).
    • Nelson syndrome has been described as corticotroph tumor progression seen in patients who had bilateral adrenalectomy as radical treatment for Cushing disease. In a retrospective study looking at 53 Cushing disease patients who underwent bilateral adrenalectomy without pituitary irradiation, [4] corticotroph tumor progression was noted to be present in half of the patients, mostly within 3 years of surgery. Patients with a shorter duration of Cushing disease and a high plasma ACTH concentration in the year after adrenalectomy were more likely to develop Nelson’s syndrome. Enlarging corticotroph tumor can manifest clinically with compressive symptoms such as headache, vision change, ocular palsy and hyperpigmentation due to very high ACTH concentrations.
  • Ectopic ACTH secretion is caused by small-cell lung tumors, carcinoid tumors, or other tumors with neuroendocrine origin. These tumors themselves can secrete ACTH, which subsequently stimulates the adrenal glands to make more cortisol.
  • Ectopic CRH secretion leading to increased ACTH secretion comprises a very rare group of cases of Cushing syndrome. [2]
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Epidemiology

Identifying the exact incidence of Cushing syndrome is challenging because patients can present with a wide spectrum from subclinical, mild, cyclic, to severe Cushing syndrome. Therefore, the true incidence might be underestimated. In a European population based study, the annual incidence of endogenous Cushing syndrome was reported to be 1.2-1.7 per million per year (Cushing disease), 0.6 per million per year (adrenal adenoma), and 0.2 per million per year (adrenal carcinoma). [5]

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 higher incidence of lung tumors in this population.

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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Prognosis

Mortality in patients with Cushing syndrome was reported to be twice more than those without.{ref 6} A systematic review and meta-analysis in 2012 has shown that Cushing disease patients with persistent disease after surgery had higher mortality than those with initial remission and Cushing syndrome due to a benign adrenal adenoma. [6]

Morbidity and mortality associated with Cushing syndrome are related primarily to the effects of excess glucocorticoids. Exposure to excess glucocorticoids results in multiple medical problems, including hypertension, cardiovascular disease, obesity, osteoporosis, fractures, impaired immune function, impaired wound healing, glucose intolerance, and psychosis. A large primary pituitary tumor may also cause panhypopituitarism and visual loss. Prognosis is favorable if surgery is curative. The rare adrenocortical carcinomas are associated with a 5-year survival rate of 30% or less. Catastrophic medical crises such as perforated viscera [7] and opportunistic fungal infections [8] can occur in glucocorticoid excess states. High levels of endogenous glucocorticoids may mask the abdominal symptoms associated with catastrophic abdominal events such as perforated bowel.

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.

Other potential complications associated with Cushing syndrome include the following:

A study by Davi' et al found that in ectopic Cushing syndrome, prognosis is influenced by the type of neuroendocrine tumor causing it, as well as by grading, the presence of distant metastases, the severity of the hypercortisolism, the existence of hypokalemia, and the presence of diabetes mellitus. The investigators also determined that survival and surgical cure rates are better for bronchial carcinoids than for occult tumors and pancreatic neuroendocrine tumors. [9]  

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Patient Education

Patients should be educated about adrenal crisis.

Instruction on specific medication use is indicated.

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