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Essentials in  Cushing's disease and Nelson's syndrome:

Nelson's syndrome take place only after bilateral adrenalectomy.
 Cushing disease is serious and if untreated, the main survival rate is 5 years.
The best initial treatment of Cushing's disease and Nelson's syndrome is transsphenoidal elective resection of the tumour, regardless of the size.

 
 

The tissue effects of chronic hypercortisolism that result in Cushing's syndrome may be caused by adrenal tumors, ectopic secretion of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH), severe depression, exogenous administration of glucocorticoids, or pituitary hypersecretion of ACTH. Pituitary-dependent hypersecretion of ACTH results in two clinical conditions that are of particular interest to the neurosurgeon - Cushing's disease and Nelson's syndrome. Cushing's disease is the hypersecretion of ACTH by a pituitary source, usually a pituitary adenoma, that causes bilateral adrenal cortical hyperplasia and consequent hypercortisolism. Nelson's syndrome, which some patients develop after undergoing adrenalectomy for the treatment of Cushing's disease, is the hypersecretion of ACTH by a pituitary adenoma that results in cutaneous hyperpigmentation. Nelson's syndrome differs from Cushing's disease in that the hypercortisolism cannot occur because of the adrenalectomy and, by definition, a pituitary tumour is known to be present.

Historical Perspective

In 1932, Cushing reported his detailed study of 12 patients who manifested signs of hypercortisolism during their lifetime. On the basis of the demonstration of pituitary basophilic adenomas in six of the eight patients studied at autopsy, Cushing suggested that there was a causal relationship between the pituitary tumour and the characteristic bilateral adrenocortical hyperplasia. A year later, Howard Naffziger performed the first craniotomy for removal of a pituitary adenoma in a patient with Cushing's disease. The resection produced a dramatic resolution of symptoms, but despite postoperative pituitary irradiation, the patient's disease recurred and she died seven years after the operation. The convincing implication of a link between pituitary adenoma and hypercortisolism provided by this case and subsequent case studies did not dispel scepticism that a pituitary adenoma was the primary defect in Cushing's syndrome. These doubts were based on the high incidence (10 to 20 percent) of asymptomatic basophilic pituitary adenomas found at autopsy and on the inability to distinguish biochemically between the different causes of hypercortisolism. In addition, the available radiologic techniques were not sensitive enough to detect small pituitary tumors. Many investigators believed that the primary defect lay in the adrenal glands. After the introduction of cortisone in 1950, adrenalectomy became the preferred mode of therapy for all cases of Cushing's syndrome.

The efficacy of pituitary irradiation in some cases of hypercortisolism, the lack of consistent pathologic findings among patients who underwent adrenalectomy, and the recognition of Nelson's syndrome fostered renewed interest in the concept of a pituitary origin. These observations supported the notion that at least two types of Cushing's syndrome exist, one of adrenal origin and one of pituitary origin. Clayton, in 1958, may have been the first to provide direct evidence of pituitary hyperfunction in Cushing's syndrome by her report of two patients with elevated plasma ACTH levels who were found to have pituitary tumors and adrenal hyperplasia. In the same year, Nelson reported the development of a pituitary tumour, hypersecretion of ACTH, and cutaneous hyperpigmentation in a patient who had undergone bilateral adrenalectomy for the treatment of Cushing's syndrome. In that case, surgical removal of the pituitary adenoma resulted in resolution of the hyperpigmentation and apparently complete resolution of ACTH hypersecretion, as reflected in the finding of no detectable ACTH in the plasma. The subsequent report by Salassa and colleagues substantiated Nelson's findings and provided radiologic evidence that, in some patients, a pituitary tumour was present before adrenalectomy. These authors suggested that approximately 10 percent of patients undergoing adrenalectomy for Cushing's syndrome would subsequently develop signs of a pituitary tumour and cutaneous melanosis. Their findings also emphasized the existence of complex feedback loops between pituitary corticotropes and the adrenal gland.

Subsequent clarification of the different biochemical factors involved in the development of Cushing's syndrome has permitted development of therapies specific for the causes of hypercortisolism in most patients. These endocrinologic methods and the results obtained with pituitary microsurgery, which can achieve lasting remission of disease while preserving normal pituitary function after the selective removal of a corticotropic adenoma, have firmly established Cushing's disease as a distinct clinico-pathologic entity.

Pathogenesis

The pathophysiology of Cushing's disease is as complex as Cushing predicted in summarizing his cases as being "so many and varied as to baffle analysis." Although the hormonal mechanisms that produce the observed clinical features are still poorly understood, it is known that chronic exposure of tissues to excessive quantities of cortisol, which influences cytoplasmic and nuclear receptors, results in Cushing's syndrome. At least two-thirds of all cases of Cushing's syndrome can be ascribed to a pituitary cause and are examples of pituitary Cushing's syndrome (Cushing's disease). ACTH-secreting nonpituitary neoplasms that cause secondary hypercortisolism (ectopic Cushing's syndrome) and the adrenal disorder causing primary hypercortisolism (adrenal Cushing's syndrome) are responsible for approximately equal proportions of the majority of remaining cases of spontaneous Cushing's syndrome.

The periodic or continuous oversecretion of ACTH (corticotropin) by a pituitary source is now recognized as the hormonal dysfunction underlying Cushing's disease. There is loss of the normal diurnal secretory pattern and reduced sensitivity of the hypothalamus and normal pituitary to glucocorticoid feedback suppression. The increased stimulation of the adrenal cortices causes hyperplasia and secondary hypercortisolism. On occasion the hyperplasia can be nodular. Plasma ACTH levels usually are normal or modestly elevated in the presence of a high serum cortisol level. High levels of serum cortisol cause suppression of ACTH secretion by both normal and neoplastic corticotropes, which is the basis for the use of dexamethasone suppression tests in the diagnostic differentiation of Cushing's disease from other causes of Cushing's syndrome. Perhaps in synergy with the overproduction of ACTH, the adrenal glands are also more sensitive to stimulation by ACTH.

Hypercortisolism is associated with increased intravascular. intercellular, and intracellular volume, which possibly is related to increased mineralocorticoid effects. In addition to abnormalities in volume, normal plasma renin levels and enhanced vascular reactivity probably contribute to the hypertension that is present in up to 75 percent of patients. The increased mineralocorticoid effects may lead to hypokalemic alkalosis. The glucose intolerance often observed may be due to partial blockade of insulin receptors by excess cortisol, and an increase in gluconeogenesis and glycolysis. Hypercortisolism may also induce a central hypothyroidism. Hyperlipidemia and hypertension seem to contribute to the accelerated atherosclerosis and cardiac disease seen in Cushing's disease.

Among patients with Cushing's disease, as many as 80 percent have a pituitary adenoma. Other pituitary lesions reported in association with the disease include diffuse or multinodular hyperplasia of corticotropes; multiple, separate pituitary adenomas; co­existing corticotrope hyperplasia and adenoma; and gangliocytoma and adenoma. In some cases, total hypophysectomy has resulted in remission of disease, and serial sections through the excised gland have revealed no abnormality. These variations in the pathology of the pituitary, along with clinical data suggesting that certain neurotransmitters may influence the course of the disease, have been considered evidence that hypothalamic dysfunction is a factor in some cases of Cushing's disease. Additional support for the role of hypothalamic dysfunction may be found in those cases that respond to medications, such as bromocriptine, somatostatin, and sodium valproate, that inhibit the secretion of CRH; in examples of cyclical Cushing's disease; and in patients with psychiatric disorders that present with a Cushing's disease-like syndrome. In addition, the rare occurrence of pituitary adenoma mixed with intrasellar gangliocytoma does suggest that neuronal dysfunction may be involved in the development of some adenomas. However, the failure of pituitary stalk sectioning to prevent ACTH hypersecretion or to induce remission of Cushing's disease seems to contradict the theory of a hypothalamic cause in some cases of Cushing's disease. Furthermore, the return of normal pituitary function after a prolonged period of hypocortisolism following selective removal of a pituitary microadenoma implies that the hypothalamus and normal pituitary corticotropes were chronically suppressed rather than hyperactive in the CRH or inhibitory factors have a role in the pathophysiology of Cushing's disease or Nelson's syndrome is not conclusive. None­theless, excess CRH, and thus Cushing's disease, could result from a hypothalamic disorder or an ectopic neoplastic source. Despite the ongoing debate about the role of the hypothalamus in the pathogenesis of Cushing's disease, pituitary tumors are considered its main cause.

In Nelson's syndrome, the loss of partial cortisol inhibition as a consequence of the adrenalectomy allows the pituitary tumour to secrete tremendous amounts of ACTH and may also promote growth of the adenoma. The resulting high plasma levels of ACTH and other factors stimulate cutaneous melanocytes to produce the hyperpigmentation characteristic of this condition; β-lipotropin (βLPH) and melanocyte-stimulating hormone have not been convincingly shown to contribute to the hyperpigmentation. In contrast to Cushing's disease, the tumors of Nelson's syndrome usually do not show suppression of ACTH secretion in response to the administration of high-dose dexamethasone. This difference is presumably a consequence of prolonged "inadequate" cortisol stimulation (suppression of corticotropes) after the adrenalectomy.

The corticotropic pituitary adenomas responsible for the hypersecretion of ACTH are most often microadenomas averaging 5 mm in diameter. In Nelson's syndrome more often than in Cushing's disease (approximately 50 percent compared to less than 20 percent of cases, respectively), the responsible tumour is a macroadenoma, occasionally one with invasive tendencies. The typical corticotropic adenoma can be recognized intraoperatively as soft, sometimes semiliquid, white-to-reddish tissue that is distinct from the more firm, yellowish normal anterior lobe. However. the adenoma may be difficult to distinguish from the posterior lobe. Although it has been suggested that corticotropic adenomas have a predilection for the central mucoid core of the anterior lobe, they may be located anywhere in the sella. Lamberts and colleagues have suggested that corticotropic adenomas originate in either the anterior or the intermediate lobe. They postulated that tumors originating within the intermediate lobe contain interspersed axons, are sensitive to a dopamine agonist, have a greater tendency toward recurrence after surgery, and are an expression of hypothalamic dysfunction. The retrospective thorough evaluation of 15 cases by Raffel and colleagues failed to reveal axons in any of the tumors studied. Other reports of patients with bromocriptine-responsive Cushing's disease have also raised doubt regarding an intermediate lobe origin.

Microscopically, corticotropic tumors are composed of compact sheets of uniform polygonal cells having round to oval nuclei with prominent nucleoli. Often there is a radial arrangement of tumour cells around capillaries. The surrounding gland and acini are compressed or destroyed, and the tumour may or may not be well circumscribed. There are usually no mitoses or other signs of malignancy, but local invasiveness, subarachnoid dissemination, and distant metastasis occur more frequently with corticotropic tumors than with any other pituitary adenoma. although they are still quite rare. When examined with routine histologic techniques, the tumour cells may exhibit the classic basophilic staining reported by Cushing. These densely granulated cells stain positively with periodic acid Schiff (PAS) stain and lead hematoxylin and usually are indistinguishable from normal corticotropes. The long-standing classification of pituitary tumors as chromophobic, basophilic, or eosinophilic is known to be inadequate, in that these designations have no correlation with the in vivo secretory product, activity, or cellular origin of the lesion. A review of Cushing's original report and subsequent experience indicates that the tumors may also be chromophobic, mixed, or eosinophilic. Variations in the histologic appearance of the cells may be a result of minor differences in staining technique, but they may in some cases relate to the volume of secretory granules within the tumour cells. Tumors are now classified according to the secretory product or the cell of origin (e.g., lactotrope, somatotrope, corticotrope).

Ultrastructural and immunohistochemical studies of corticotropic adenomas reliably reveal distinct identifying features. Characteristically, there are spherical or slightly irregular dense­cored secretory granules that average 450 nm in diameter and tend to line up along cell membranes. These granules stain selectively when anti-ACTH and anti-,β-lipotropin immunohistochemical techniques are used. Also characteristic is the presence of bundles of microfilaments, 7 nm in diameter, arranged in a perinuclear distribution. Robert and colleagues believe that these perinuclear microfilaments represent the ultrastructural basis for Crooke's hyaline change. When examined by light microscopy, Crooke's hyaline change is seen only in non adenoma corticotropes, and only when hypercortisolism is present. The microfilaments are found in minimal numbers in the tumour and normal corticotropes of Nelson's syndrome, presumably because there is no hypercortisolism to induce their deposition. Secretory granules may be slightly smaller (approximately 200 nm) and ribosomes more prominent, but otherwise there are minimal ultrastructural differences between normal corticotropes and the adenoma corticotropes of Nelson's syndrome. Reuss and colleagues have, however, been able to find subtle ultrastructural differences between well-differentiated and undifferentiated ACTH-secreting adenomas in Cushing's disease and Nelson's syndrome.

Even though there are no well-established criteria for the diagnosis of corticotrope hyperplasia, it is claimed that this condition accounts for as many as 25 percent of cases of Cushing's disease in some series. These reports contrast markedly with other series in which there have been no instances of corticotrope hyperplasia. In Wilson's series of 216 patients treated with microsurgery for Cushing's disease, only two cases of diffuse hyperplasia were identified, both of which responded to selective surgery. Definitive criteria for the recognition of this entity have been proposed by McKeever and colleagues in their report of a case of Cushing's disease resulting from multinodular corticotrope hyperplasia. In general, one expects to find an increase in ACTH-laden corticotropes interspersed among fewer than 10 percent of non corticotrope secretory cells, and no evidence of compressed or destroyed acini. Expanded acini may be seen if the process is focal. Light microscopy should show no evidence of Crooke's hyaline change in the areas of suspected hyperplasia.

Clinical Features

Cushing's disease is a serious endocrinopathy, the natural course of which is unpredictable. Occasionally Cushing's disease resolves spontaneously, but resolution can be followed by relapse months or years later. In some cases, expression of Cushing's disease is cyclical. Of the hypersecretory pituitary disorders, Cushing's disease has the highest incidence of morbidity and of persistence after therapeutic intervention. Untreated, the fully active disease has been associated with a 5-year survival rate of less than 50 percent. Death most often results from cardiovascular or infectious complications. Women constitute over 75 percent of patients with Cushing's disease; in contrast, there is a predominance of children (65 percent) in cases of adrenal Cushing's syndrome and of men (60 percent) in cases of ectopic Cushing's syndrome. Most patients with Cushing's disease are between 30 and 40 years old at the time of diagnosis.

No one clinical feature is diagnostic of Cushing's disease, and the clinical presentation is diagnostic in less than 50 percent of cases. The classic findings are moon facies, centripetal obesity, buffalo hump, hypertension, thin skin, purple abdominal striae, and ecchymoses. Frequently the patients have emotional disorders, most often depression and psychosis, as well as menstrual irregularities or impotence, osteoporotic back pain, and symptoms referable to glucose intolerance. Patients may also have osteoporosis, proximal muscle weakness, decreased collagen formation, hypercholesterolemia, and impaired immune function. Occasionally, patients present with hypokalemic alkalosis and kidney stones. Patients with a variety of psychiatric disorders (e.g., depression, anorexia nervosa, and chronic anxiety), drug dependence, or glucocorticoid resistance may present with symptoms and signs that mimic Cushing's disease. The prominent supraclavicular and mandibular fat pads seen in cases of Cushing's disease are not present in the "pseudocushingoid" patient with exogenous obesity who occasionally presents with complaints and laboratory findings suggestive of Cushing's disease.

Other hormones probably contribute primarily or secondarily to the clinical syndrome For example, plasma testosterone, presumably from the adrenals, is significantly elevated in females who have Cushing's disease and may contribute to hirsutism, acne, and mental disorders. In contrast, testosterone is usually reduced to less than one-third normal in males, which may be the cause of oligospermia and impotence. Growth hormone secretion during sleep and in response to provocative stimuli such as growth hormone releasing hormone is significantly blunted in patients with Cushing's disease. The secretion of other pituitary hormones, such as prolactin and thyroid stimulating hormone, is often abnormal in Cushing's disease, and the hypersecretion seems unrelated to the mass effect in those cases with an adenoma. The role of galanin, which may influence the secretion of other pituitary hormones and is mainly found in corticotropes, is being investigated. A clear hormonal basis for the hypertension is yet to be demonstrated. In many cases, hypertension, mental illness, and obesity persist despite adrenalectomy.

In comparison with the symptoms of endogenous Cushing's disease, only obesity, acne, and mental symptoms (typically hyperactivity and elation) occur as frequently in patients who are given high-dose glucocorticoids (exogenous Cushing's syndrome) as part of a therapeutic regimen for unrelated disease. In this same group, less than 29 percent of patients develop hypertension, and hyperpigmentation does not occur at all. A similarly low incidence of hypertension is noted in patients with ectopic Cushing's syndrome, despite the fact that they have the highest levels of ACTH and cortisol observed in any of the groups. However, in 25 percent of cases of ectopic Cushing's syndrome, cutaneous hyperpigmentation occurs.

Nelson's syndrome appears unpredictably months to years after adrenalectomy; its incidence is highest in patients who underwent adrenalectomy during childhood. so Nelson's syndrome seems to occur as frequently in men as in women, but its incidence may be less among patients who receive pituitary irradiation after their adrenalectomy. The incidence of Nelson's syndrome is also significantly reduced if autotransplantation of adrenal tissue is performed at the time of bilateral adrenalectomy. A history of Cushing's syndrome that has been treated by adrenalectomy in a patient who complains of increased cutaneous pigmentation and has an enlarged sella turcica is diagnostic of Nelson's syndrome. Compared to patients with Cushing's disease, who have a very low incidence of headaches or visual symptoms, those with Nelson's syndrome are more likely to have headaches or visual system impairment as a consequence of a mass effect or tumour invasion. A significant proportion of patients with Nelson's syndrome have died from the direct effects of their tumors.

Diagnostic Evaluation

The diagnosis of Cushing's disease is established by endocrinologic criteria. If doubt regarding the cause persists, or if microsurgical exploration of the pituitary is unrewarding and total hypophysectomy is contraindicated, selective venous sampling for ACTH should be performed. Plasma ACTH levels in samples from either the cavernous or the inferior petrosal sinus, the jugular bulb, the thyroidal veins, and the superior and inferior vena cava are compared with a peripheral venous sample obtained simultaneously. An inferior petrosal sinus to peripheral ACTH ratio of more than 2: I is generally a reliable indicator of Cushing's disease and may support a recommendation of partial or total hypophysectomy for a patient in whom a negative pituitary exploration has been performed. Because of variations in the venous drainage of the pituitary and cavernous sinuses, bilateral petrosal sampling should be performed, but it should not be relied on to indicate lateralization of the tumour when positive. Yanovski and colleagues also caution against the use of petrosal sinus sampling to distinguish between patients with mild Cushing's disease and pseudo-Cushing's states.

In the past, the radiologic evaluation of the sella employed hypocycloidal poly tomography and high-resolution computed tomography (CT) scanning with sagittal and coronal reformations. These studies can delineate the sella and localize focal abnormalities. Unfortunately, the high incidence of incidental bone abnormalities found on poly tomography and of nonspecific changes in pituitary parenchymal attenuation seen on CT scans emphasize the need to rely on endocrinologic criteria for diagnosis. In patients subsequently proved to have Cushing's disease, high-resolution CT scanning may demonstrate an abnormality consistent with an adenoma in as few as 25 percent and with an accuracy of approximately 39 percent. Magnetic resonance imaging with gadolinium enhancement, currently the radiographic procedure of choice, has a higher sensitivity, approximately 55 to 100 percent, for visualizing adenomas in Cushing's disease. If endocrinologic criteria are met, radiologic studies showing no abnormalities should not dissuade the surgeon from performing a trans-sphenoidal exploration.

Medical Management

For the patient with Cushing's disease or Nelson's syndrome who is not considered a candidate for surgical intervention or who has an unresectable or incompletely treated tumour, medical therapy may be an option. Medical therapy is only palliative, however, and should be reserved for use in preparation for surgery, in conjunction with pituitary irradiation, or after both these modalities have failed to achieve a cure. Drug therapy is directed at reducing the secretion of ACTH by the pituitary or at interrupting adrenal steroidogenesis.

Cyproheptadine, a serotonin antagonist, and bromocriptine, a dopaminergic agonist, are thought to alter hypothalamic neuro­transmitters that regulate CRH. It is also possible that cyproheptadine exerts direct effects on pituitary corticotropes. Cyproheptadine reportedly has achieved remission in more than 50 percent of patients with Cushing's disease. A dosage of 24 mg/day is attained gradually; if it is effective, chemical and clinical remission should be evident within 2 to 6 months. A relapse while the patient is under treatment, and the side effects of somnolence and hyperphagia-especially in children - may limit the usefulness of the drug in some cases. Results reported with the use of bromocriptine to treat Cushing's disease have been contradictory.  Lamberts and colleagues have presented evidence that patients whose corticotropic adenomas originate in the intermediate lobe suppress ACTH secretion in response to 10 mg per day of bromocriptine. After discontinuation of cyproheptadine or bromocriptine therapy, a relapse can be expected in virtually all cases. The recent finding that naloxone, somatostatin analogues, sodium valproate, and reserpine may selectively suppress corticotropin hypersecretion in patients with Cushing's disease, Nelson's syndrome, or Addison's disease may indicate other avenues for improved medical therapy in the future.

Ketoconazole, aminoglutethimide, metyrapone, o.p'-dichloro­diphenyldichloroethane (o.p'-DDD), and trilostane have been used effectively to direct pharmacologic therapy to the adrenal cortices. These adrenoactive agents do not suppress either the secretion of ACTH or the growth of the pituitary lesion. ACTH levels in plasma may increase during effective anti adrenal therapy in a manner analogous to the increase of ACTH levels in patients with Addison's disease or during the development of Nelson's syndrome. Although o.p'-DDD is toxic to the adrenal cortices, it has been used at a reduced dosage to block steroidogenesis chronically. Its side effects include sedation, depression, gastrointestinal problems, and permanent adrenal damage. Aminoglutethimide, which inhibits the conversion of cholesterol to pregnenolone, blocks the first step in steroidogenesis. It has been used successfully alone as well as in combination with metyrapone. Metyrapone blocks the 11-hydroxylase step in cortisol production, and can provide long-term control of the hypercortisolism. Hirsutism and hypertension have been a problem with the prolonged use of metyrapone, and 20 to 30 percent of patients develop skin rash, hypothyroid goiter, somnolence, dizziness, blurred vision, or gonadal toxicity while taking aminoglutethimide. Mineralocorticoid and glucocorticoid replacement is required with the use of o.p'-DDD or aminoglutethimide. Ketoconazole, an antifungal agent, has been found to be particularly useful in blocking hypercortisolism. It inhibits steroidogenesis at several sites, and generally is well tolerated. Its side effects include hepatoxicity, gastrointestinal effects, skin rashes, and gynecomastia in men. The antiprogesterone agent RU 486 may also have efficacy in the symptomatic treatment of hypercorticolism caused by Cushing's disease.

Radiation and Surgical Therapy

The goals of definitive therapy should be (1) to eliminate the inappropriate secretion of ACTH and hypercortisolism; (2) to eradicate the responsible lesion; and (3) to prevent permanent dependence on hormone replacement by averting endocrine deficiency.

As primary therapy, irradiation of the pituitary gland, either with heavy particles or from a megavoltage source, produces remission of disease in 50 to 80 percent of patients with Cushing's disease, and in a much smaller percentage of those with Nelson's syndrome. Children appear to respond better than adults to this form of therapy. The efficacy of pituitary irradiation, however, is qualified by the delay in hormonal response and by the risk of radiation damage to normal structures included in the treatment fields. In addition, most patients who undergo radiation therapy subsequently develop some degree of hypopituitarism. In many cases, pituitary irradiation is used in addition to medical measures to control hypercortisolism, Low-dose external pituitary irradiation for the treatment of Cushing's disease has been found to have relatively poor efficacy.

Selective microsurgical removal of corticotropic microadenomas has proved to be the most effective way to achieve the goals of definitive therapy. The refinement of transsphenoidal pituitary microsurgery constitutes the single most important advance contributing to the successful treatment of Cushing's disease and Nelson's syndrome. When performed by an experienced surgeon, this procedure has a very low incidence of morbidity and mortality.

The microadenomas are rarely located on the surface of the anterior lobe, and often must be exposed by a systematic, thorough dissection through an apparently normal gland. In exceedingly rare instances, a microadenoma is found outside the pituitary gland. For consenting adults, total hypophysectomy should be considered an option if no abnormality is demonstrated at the time of operation, as an undetectably minute adenoma may be presumed to be the source of disease. Craniotomy should be restricted to those cases in which parasellar extension of tumour or a small sella turcica precludes adequate access to a large suprasellar tumour by the transsphenoidal route. Adrenalectomy should be used only as a last resort, after pharmacologic therapy, pituitary surgery, and irradiation have failed to produce a cure.

The results of transsphenoidal microsurgical management of ACTH-secreting pituitary tumors derived from large representative reports in the literature indicate that the rate of remission obtained by selective removal of a microadenoma can be greater than 90 percent. Extrasellar extension of tumour, macroadenomas, the failure to demonstrate tumour, the presence of Nelson's syndrome, or any combination of these, is associated with a poorer outcome. In addition, there are still cases in which an ectopic cause of Cushing's syndrome masquerades as Cushing's disease, and results in a failure to respond to pituitary microsurgery. In each series, long-term remission. of disease was associated with a prolonged (more than 3 months) period of hypocortisolism after successful microsurgery; during this period, steroid replacement was required for at least 6 months. Hypopituitarism occurred only in those patients in whom hypophysectomy was performed intentionally. Among patients initially considered cured, approximately 5 to 10 percent will have tumour recurrence. Overall long-term follow-up suggests that 64 to 83 percent of patients can be cured with transsphenoidal microsurgery.

In contrast, less than 30 percent of patients with Nelson's syndrome who undergo surgery can be expected to have remission of disease, regardless of tumour size. The high incidence of cranial nerve dysfunction, the tendency toward invasion of surrounding structures by tumour, and the poor response to all treatment modalities associated with Nelson's syndrome emphasize that adrenalectomy should be used to treat Cushing's disease only after all other therapy has failed.

The specificity of transsphenoidal microsurgical exploration of the pituitary gland and the high likelihood of cure following selective transsphenoidal microsurgery make this approach the present treatment of choice. It should be the primary treatment for all patients with Cushing's disease or Nelson's syndrome.

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