Teorías de aprendizaje Desde sus inicios el hombre sintió la

Cushing's syndrome results from chronic exposure to excessive amounts of glucocorticoid hormones.

Clinical spectrum of adrenal gland pathology 

The disease is rare with annual incidence of 5 to 6 cases per million population. Significantly more fre- quent is iatrogenic (exogenous) Cushing's syndrome due to use of synthetic glucocorticoids for therapeutic purposes (10).

Cessation of normal functioning of negative feedback of hypothalamic-pituitary-adrenal axis and loss of circadian rhythm of cortisol secretion are two key events in the development of the disease. Since there are several causes for this, it is appropriate to roughly divide endogenous Cushing's syndrome into the ACTH dependent and independent forms. In the for- mer, excessive secretion of ACTH from the pituitary adenoma or ectopic neuroendocrine tumor leads to bilateral hyperplasia of the adrenal cortex. The most common forms of ACTH independent Cushing's syn- drome are adenoma and carcinoma of the adrenal cortex, while ACTH independent macronodular adre- nal hyperplasia and primary pigmented nodular adre- nal hyperplasia are much rarer (11).

Clinical picture might be variable and sometimes the disease is not obvious at first glance. Typical patients are obese with fat redistribution to the trunk (central obesity), thin limbs and a round, red face (moon face). Additionally, fat might accumulate at back of the neck (buffalo hump) and in supracla- vicular regions. Females can become hirsute with frontal hair thinning and acne. Menstrual cycle is often irregular (oligomenorrhea), while loss of libido and potency is common in men. Psychiatric disorders occur in half of the patients, regardless of the cause. Excessive fatigue, depression or increased irritability are most prevalent, however paranoid psychosis is also possible. Proximal muscle weakness develops and patients might sustain osteoporotic vertebral and rib fractures. Hypercalciuria may lead to the forma- tion of kidney stones. Skin bruising after minimal injuries is quite typical. Common skin changes in- clude also telangiectasias and prominent, more than 1 cm wide purple stretch marks on the abdomen, thighs, breasts and upper arms, while hyperpigmen- tation can develop only in forms that are ACTH dependent. Infections, particularly fungal, are more common than usual, and poor wound healing is also typical. High blood pressure is present in most patients with similar propensity for venous thromboembo- lisms. Impaired glucose tolerance or even secondary diabetes are common. Laboratory might also show combined hyperlipidemia and hypokalemic metabolic alkalosis. Patients may develop glaucoma, as well as retro-orbital exophthalmos due to accumulation of fat. If Cushing's syndrome is caused by ectopic ACTH secretion from the fast growing small cell lung carcinoma, the patient may seem as if he had

Addison's disease, because of dark pigmentation of his skin caused by high concentrations of ACTH in combination with rapid physical decline due to the underlying disease. Similarly, some patients with adrenal cortical carcinoma do not have typical clinical signs of endocrine disease, but only local problems in terms of pain or a feeling of fullness in the abdo- men (12).

Step-by-step diagnostic approach is recommended. The first step is to confirm the presence of excessive cortisol secretion. This diagnosis is most easily made by the low-dose dexamethasone suppression test, by measuring late-night serum (or salivary) cortisol levels and by 24-hour urine collection to measure free cortisol levels.

Once the diagnosis is established, the next step should determine if the disease is ACTH-dependent or ACTH-independent. This is done by measuring plas- ma ACTH. An undetectable ACTH is diagnostic of ACTH-independent Cushing’s syndrome, so adrenal CT or MR scan should follow. If ACTH is not suppressed, we must determine whether the source of ACTH secretion is in the pituitary gland or ectopic. All such patients should undergo a contrast- enhanced MR of the pituitary. If there’s no clear tumor, inferior petrosal sinus sampling may be useful to prove the pituitary source of ACTH. Octreo- tide scintigraphy, positron emission tomography, chest and abdominal CT or MR scans could be per- formed in patients with suspected ectopic ACTH production to find the underlying tumor (11).

Treatment should be oriented towards the underlying cause, if possible. For patients with pituitary ACTH adenoma transsphenoidal operation is the primary treatment modality. In the event of surgical failure ACTH could be lowered by the new somatostatin analogues in combination with cabergoline or by radiotherapy with gamma knife (13). The last option is bilateral adrenalectomy which puts patients at risk for Nelson's syndrome, a condition caused by significant growth of ACTH adenoma (14). Optimal treatment of ectopic Cushing's syndrome is resection of the underlying tumor. If this is not possible inhi- bitors of cortisol synthesis are an option, followed by bilateral adrenalectomy if needed. Patients with cortisol-producing adrenal adenomas will be cured by unilateral adrenalectomy, while those with adrenal carcinomas have around 50% chance of recurrence after an apparently successful resection, so they often need adjuvant mitotane and radiotherapy. Untreated Cushing's syndrome is often fatal due to cardiovascular and thromboembolic complications. Patients are also endangered by opportunistic bacterial

Clinical spectrum of adrenal gland pathology 

and fungal infections. Successful operation of the adrenal tumor or the source of ACTH excess causes a transient insufficiency of the hypothalamic-pituitary- adrenal axis (10).