The treatment of choice for pituitary ACTH-dependent Cushing disease is the microsurgical removal of microadenomas or macroadenomas. If a pituitary adenoma or microadenoma can be demonstrated by radiographic techniques, a transsphenoidal operation of the pituitary gland should be the preferred treatment. If a tumor is not detected by imaging techniques, a transsphenoidal exploration of the pituitary gland is still in order, because the tumor can be found in ˜90% of patients.73,74 and 75 Even with considerable suprasellar extension, the tumor can be resected transsphenoidally. If a tumor invades the dura, total resection may be impossible, but good remission rates of 45% to 75% have been described for these cases. The microsurgical transsphenoidal selective resection of ACTH-secreting pituitary microadenomas is the most common treatment of Cushing syndrome and comes closest to the ideal form of treatment for this condition.76,77 and 78 Several reports have described a high cure rate with transsphenoidal surgical treatment of Cushing disease.73,74 and 75,79,80 The probability of finding pituitary pathology and of surgically correcting the disease is highest among patients with a typical endocrine testing pattern.81 Typical diagnostic criteria for Cushing disease consist of elevated basal urinary 17-hydroxycorticosteroids and free cortisol levels, cortisol secretion rates, and mean basal serum cortisol levels; a positive response to metyrapone (i.e., elevated ACTH levels associated with a rise in urinary 17-hydroxycorticosteroids); and abnormal suppression with low-dose dexamethasone but >50% suppression with high-dose dexamethasone. Patients with atypical diagnostic criteria have elevated basal levels but do not respond as described to metyrapone or to low or high doses of dexamethasone. Pituitary disease was found in 18 of 19 patients with typical preoperative endocrine test results but in only 6 of 11 patients with atypical test results.

If a microadenoma can be identified and totally and discretely resected, then the remaining pituitary tissue remains functional, and patients can enjoy remission without loss of endocrine function.82 If a specific adenoma cannot be identified during surgery, the decision must be made as to whether to perform a partial or total hypophysectomy. If preoperative inferior petrosal sinus sampling has been carried out and is clearly lateralizing, an appropriate hemiresection of the hypophysis should be performed. If the endocrine studies strongly indicate a pituitary origin but the petrosal sinus sampling is not lateralizing and the patient does not wish to have children, a total hypophysectomy should be considered, but only after a lengthy preoperative discussion with the patient regarding this possibility. If the patient wishes to have children, alternative forms of therapy, including medical treatment or a total adrenalectomy, must be considered. Transsphenoidal surgery for Cushing disease seems to be a reasonably safe procedure, with a mortality rate of <1%. Main complications in these patients are anterior pituitary insufficiency, which occurs in 19%, and diabetes insipidus, which occurs in 18%. Overall incidence of cerebrospinal fluid fistulas is 4%. Other complications, including meningitis, carotid artery injuries, loss of vision, and hypothalamic injuries, occur in from 1% to 2% of patients. An inverse relationship is found between the experience of the surgeon and the likelihood of complications. A statistically significant decreased incidence of morbidity and death has been reported after 200 and even 500 transsphenoidal operations have been performed.83 With transsphenoidal surgery, permanent anterior or posterior pituitary hormone deficiencies are rare. Transient diabetes insipidus may occur during the early weeks after surgery. Permanent diabetes insipidus and cerebrospinal fluid rhinorrhea are uncommon complications with an initial procedure but may occur more commonly with repeated transsphenoidal surgery. Treatment failures are most common in patients with pituitary macroadenomas or in those in whom a distinct microadenoma has not been found.

When transsphenoidal surgery has failed or alternative forms of treatment are desired, pituitary irradiation is an option. The most widely used type of pituitary irradiation is high-voltage irradiation provided by cobalt-60 (⁶⁰Co). The total recommended dose is 40 to 50 Gy, and favorable results can be achieved in ˜50% of patients.70 The best responses are observed in patients with the juvenile form of the disease or in adults younger than 40 years.

When successful, ⁶⁰Co irradiation has several advantages. Remission occurs with preservation of pituitary and adrenal function; panhypopituitarism seldom develops; normal reproductive function is restored when the patient is in remission; corticosteroid replacement therapy is not needed; recurrence is rare; and normal cortisol secretion may be restored (i.e., circadian rhythm, normal suppressibility on dexamethasone).87 The major disadvantage is the slow therapeutic response to pituitary irradiation; 6 to 18 months may elapse before a clinical and biochemical remission is achieved.

Treatment with ⁶⁰Co irradiation alone is not adequate in patients who have severe Cushing syndrome. Symptoms may progress if the patient waits for remission, and severe, perhaps irreversible, complications may result. Heavy particle beam irradiation and Bragg peak proton irradiation therapy, with a rate of improvement or remission as high as 80%, appears to be more effective than ⁶⁰Co irradiation in the treatment of Cushing syndrome.88,89 However, the prevalence of postirradiation panhypopituitarism is high. Implants of gold-198 or yttrium-90 yield complete or partial response in 77% of patients with Cushing disease, but the treatment is also complicated by hypopituitarism in 30% to 50% of the patients. Some reports suggest that significant disturbances of hypothalamic-pituitary function follow megavoltage therapy; these disturbances may progress to overt hypopituitarism.90