Pathophysiology of Cushing's Disease

Cushing's Disease

The term "Cushing's syndrome" is used to describe a condition resulting from long-term exposure to excessive glucocorticoids. The syndrome is most commonly caused by the therapeutic administration of exogenous glucocorticoids. The term "Cushing's disease" is reserved for Cushing's syndrome that is caused by excessive secretion of adrenocorticotropin hormone (ACTH) by a pituitary tumor, usually an adenoma.

Cushing's disease is a disease in which the adrenal glands overproduce certain hormones. Another medical term for this disease is hyperadrenocorticism. The adrenal glands produce several vital substances, which regulate a variety of body functions and are necessary to sustain life. The most widely known of these substances is cortisol, commonly known as cortisone. Either deficient production or excessive production of these substances may be life-threatening. Cushing's disease is a form of Cushing's syndrome that is caused by an ACTH secreting pituitary adenoma. About 10% of pituitary adenomas secrete excess ACTH. This elevated ACTH in turn stimulates the adrenal glands to produce excess cortisol. This disease process is called Cushing's disease (named after the famous neurosurgeon, Harvey Cushing).

Cushing's disease is responsible for roughly two thirds of the cases of endogenous Cushing's syndrome. The remainder of the endogenous cases are caused by ectopic ACTH-secreting tumors and primary adrenal neoplasms. Cushing's disease occurs most frequently in women of reproductive age, but it can affect males and females of any age.

There are three mechanisms by which this disease can occur. Regardless of the cause, the clinical signs are essentially the same. It is important to identify the cause, however, because the various forms are treated differently and have different prognoses.

Pituitary gland tumor. The most common cause of Cushing's Disease (85% of all cases) is a tumor of the pituitary gland. The tumor may be either benign or malignant. The tumor causes the pituitary to overproduce a hormone, which stimulates the adrenal glands. Excessive cortisone secretion results. The pituitary tumors in Cushing's disease are usually microadenomas, which, by definition, are 10 mm or less in diameter. Microadenomas generally do not cause symptoms by local mass effect. These tumors are most often discovered when clinical manifestations of hypercortisolism resulting from hypersecretion of ACTH prompt an appropriate diagnostic work-up. Occasionally, microadenomas are found incidentally during imaging performed for other reasons.

Macroadenomas are uncommon in patients with Cushing's disease. These tumors cause mass effect when their size exceeds 15 mm in diameter. Suprasellar extension and optic chiasm compression, local bone erosion, cavernous sinus compression and panhypopituitarism may occur as a macroadenoma enlarges.

Adrenal gland tumor. Cushing's Disease may be the result of a benign or malignant tumor of the adrenal gland. If benign, surgical removal cures the disease. If malignant, surgery may help for a while, but the prognosis is less favorable than for a benign tumor.

Iatrogenic. Iatrogenic Cushing's Disease means that the excess of cortisone has resulted from excessive administration of cortisone. This may occur from oral or injectable medications. Although the injections or tablets were given for a legitimate medical reason, their excess is now detrimental.

Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH. The clinical diagnosis must be based on the presence of one or more of these findings (Figure 1 showing Multiple wide striae on the abdomen of a patient with Cushing's disease.), because the syndrome itself has no true pathognomonic signs or symptoms.

The most common symptom is sudden weight gain. Obesity, usually with a central distribution, is the most frequent sign. Any sign or symptom of cortisol excess can develop initially, but muscle weakness, bruising, hypertension, facial rounding and plethora eventually occur. Hypertension is likely to develop in patients who are more than 40 years of age.

Cranial nerve III (oculomotor nerve) palsies are less well recognized, but they may occur in up to 25 percent of patients with pituitary macroadenomas and may be the lone presenting symptom in patients with pituitary adenomas. Pituitary tumors infrequently affect cranial nerves IV and VI. The mechanism for oculomotor palsies is usually direct compression by the expanding tumor as the nerve passes through the walls of the adjacent cavernous sinus. Noncompressive cranial nerve III paresis has also been reported in patients with Cushing's disease.

Another presentation or complication of Cushing's disease is opportunistic or bacterial infection. Immunosuppression resulting from corticosteroid excess is usually thought of as a cellular immune deficiency that increases the risk of opportunistic infections (Cryptococcus neoformans, Candida species, Norcardia species and other organisms). Eight of the 12 cases were complicated by bacterial infections. Subsequent case reports have further emphasized the frequency of bacterial infections in Cushing's disease.

A number of tests are necessary to diagnose and confirm Cushing's Disease. The primary one is the ACTH Stimulation Test. If it does not confirm the diagnosis, the Low-Dose Dexamethasone Suppression Test is performed. Other tests are needed to decide which form of the disease is present. An ultrasound examination can be a valuable part of the testing process. This permits us to visualize the adrenal gland tumor and determine its size. Although some of these tests are somewhat expensive, they are necessary.

Treatment is surgery to remove the pituitary tumor, if possible. After surgery, the pituitary may slowly start to work again and return to normal. During the recovery process, cortisol replacement treatments may be necessary. Radiation treatment of the pituitary gland may also be used. If the tumor does not respond to surgery or radiation, medications to stop the body from making cortisol are given. Untreated, Cushing's disease can cause severe illness, even death. Removal of the tumor may lead to full recovery, but the tumor can grow back.

Pathophysiology of Cushing's Disease

When stimulated by ACTH, the adrenal gland secretes cortisol and other steroid hormones. ACTH is produced by the pituitary gland and released into the petrosal venous sinuses in response to stimulation by corticotropin-releasing hormone (CRH) from the hypothalamus. ACTH is released in a diurnal pattern that is independent of circulating cortisol levels: peak release occurs just before awakening, and ACTH levels then decline throughout the day. Control of CRH and ACTH release is maintained through negative feedback by cortisol at the hypothalamic and pituitary levels. Neuronal input at the hypothalamic level can also stimulate CRH release.

Although the adenomas of Cushing's disease secrete excessive amounts of ACTH, they generally retain some negative feedback responsiveness to high doses of glucocorticoids. Ectopic sources of ACTH, usually in the form of extracranial neoplasms, are generally not responsive to negative feedback with high doses of glucocorticoids. However, some overlap exists in the response to negative feedback between pituitary and ectopic sources of excessive ACTH.

Cushing's syndrome is categorized as ACTH dependent or ACTH independent. This division is convenient for organizing the work-up of patients with suspected hypercortisolism.

Depression, alcoholism, medications, eating disorders and other conditions can cause mild clinical and laboratory findings, similar to those in Cushing's syndrome, termed "pseudo-Cushing's syndrome." The laboratory and clinical findings of hypercortisolism disappear if the primary process is successfully treated.

Dexamethasone, an exogenous glucocorticoid, is used to test for Cushing's syndrome. This gluococorticoid does not interfere with cortisol assays but induces similar physiologic responses.