THE DIAGNOSIS and treatment of pituitary tumors has been improved by a number of recent advances. Diagnosis of hormone hypersecretion has been facilitated by the development of more sensitive and reliable assays, especially for ACTH and insulin-like growth factor I (IGF)-I. Pituitary tumors can now be visualized more accurately due to continued improvements in magnetic resonance imaging (MRI) techniques with gadolinium enhancement. Petrosal sinus sampling can be used to measure hormone levels in the venous blood draining the pituitary. This has proved helpful in the differential diagnosis of Cushing’s disease. Treatment of pituitary tumors has been improved by advances in transsphenoidal surgery and radiotherapy and by the development of remarkably effective drugs for PRL and GH-secreting tumors. The primary therapeutic objectives are to normalize levels of hypersecreted hormones and to reduce tumor size to prevent damage to normal pituitary tissue and surrounding parasellar structures, especially the optic chiasm. This short review describes our current approach to the diagnosis and treatment of hormone- and nonhormone-secreting pituitary tumors. PRL is the hormone most frequently secreted in excess by pituitary tumors. Although very high PRL levels (>250 ng/mL) are virtually always indicative of a prolactinoma, other causes of hyperprolactinemia need to be considered with more modest elevations of serum PRL levels (1). Physiological elevations of PRL are seen normally during pregnancy and lactation, as well as during sleep and with stress. A variety of drugs, most notably dopamine receptor antagonists such as the neuroleptics and metoclopramide, often cause hyperprolactinemia. Elevated PRL levels also occur in primary hypothyroidism and in renal failure. In the absence of these conditions, however, hyperprolactinemia usually indicates a hypothalamic or pituitary disorder, but not necessarily a prolactinoma. Any sellar or parasellar process that compresses the pituitary stalk and interferes with tonic dopamine inhibition of PRL secretion can lead to hyperprolactinemia. This is an important consideration therapeutically because the treatment of patients with large pituitary masses and moderately elevated PRL levels is quite different than the treatment of patients with large prolactinomas. GH-secreting tumors may also hypersecrete PRL. PRL levels are usually greater than 250 ng/mL in patients with large prolactinomas and are usually less than 100 ng/mL in patients with pituitary stalk compression. PRL levels may be only moderately elevated (<100 ng/mL) in patients with PRL-secreting microadenomas, defined as less than 10 mm in size. Patients without any obvious cause of hyperprolactinemia and with normal high resolution MRI scans are classified as having idiopathic hyperprolactinemia. Some of these patients may actually have very small prolactinomas, but the etiology of the hyperprolactinemia in many of these patients remains unclear. Patients with PRL-secreting microadenomas usually present with symptoms caused by the high PRL levels. Patients with PRL-secreting macroadenomas, however, often present with additional symptoms related to the presence of a pituitary mass lesion. The treatment of patients with prolactinomas varies with the symptoms of the patient and the size of the tumor (2). Hyperprolactinemia causes hypogonadotropic hypogonadism in women and men, primarily due to the inhibitory effect of high PRL levels on hypothalamic GnRH release. The most common symptoms of hyperprolactinemia are amenorrhea and galactorrhea in women and decreased libido and impotence in men. Treatment is clearly indicated to restore fertility and to reverse symptomatic hypogonadism. The long-term effects of hypogonadism on bone mineral density and the cardiovascular system also need to be considered. A major therapeutic objective is also to reduce the size of the tumor and to limit future growth. Reduction in tumor size is of primary importance in patients with large macroadenomas and symptoms of a mass lesion, including visual symptoms secondary to compression of the optic chiasm, cranial neuropathies, and hypopituitarism. This is not the case with microadenomas. Several studies now support the view that in the majority of patients, untreated microadenomas do not grow into macroadenomas (2, 3). Thus, the presence of a small tumor per se (in the absence of clinical symptoms) is not a definite indication for surgical intervention or for medical intervention. These patients must, however, continue to be carefully monitored. The presence of a macroadenoma, however, even without symptoms, usually warrants treatment to prevent future growth. Medical treatment with long-acting dopamine agonists is very effective in reducing PRL levels and restoring gonadal function in patients with prolactinomas. In addition, these drugs cause significant tumor shrinkage in ∼75% of patients (2, 4). In some patients with large invasive tumors, the shrinkage can be dramatic. Changes in visual fields can be noted within days after initiating therapy. However, if the dopamine agonist is stopped, hyperprolactinemia usually recurs as well as reexpansion of the tumor. Transsphenoidal surgery by an experienced pituitary neurosurgeon is also very effective in curing 70–90% of patients with PRL-secreting microadenomas (4–7). Initial enthusiasm for transsphenoidal surgery of PRL-secreting microadenomas has, however, been dampened considerably by high recurrence rates (17–50%) as well as by the effectiveness of current medical therapy with long-acting dopamine agonists (6, 7). Surgical cure rates are much lower for macroadenomas. Transsphenoidal surgery, however, continues to be used and is effective if dopamine agonists are not tolerated or if they do not work. Surgery may also be indicated for large tumors with PRL levels in the range seen with pituitary stalk compression, raising the suspicion that the lesion may be something other than a prolactinoma. Very rarely, radiotherapy may be required depending on the response to surgery and dopamine agonist treatment. The majority of patients with PRL-secreting tumors who require therapy can be safely and effectively treated with dopamine agonists. Bromocriptine and pergolide are the two long-acting dopamine agonists that have been available for use in the United States for many years. Recently, another very long-acting dopamine agonist, cabergoline, has become available in the United States. All three drugs are ergoline derivatives. Pergolide is only approved in the United States for the treatment of Parkinson’s disease, but it has been shown to be an extremely safe and effective treatment for prolactinomas (8, 9). In a large, randomized, controlled multicenter trial, pergolide and bromocriptine were shown to be equally effective in lowering PRL levels and causing tumor shrinkage (9). The advantages to the use of pergolide compared with bromocriptine are that it is much more potent, is longer-acting, and is considerably cheaper. Thus, pergolide can usually be administered in one dose of 0.05–0.1 mg at night. Bromocriptine (2.5 mg) is usually administered two to three times a day. Cabergoline is even longer-acting than pergolide and can be administered at doses of 0.5–1 mg once or twice weekly. Like bromocriptine and pergolide, it is very effective in normalizing PRL levels, restoring gonadal function, and in causing tumor shrinkage. Cabergoline was shown to be better tolerated than bromocriptine in a large double-blind comparison of the two drugs (10). In that study, 3% of patients discontinued cabergoline because of drug intolerance as compared with 12% of patients on bromocriptine. In addition, prolactinomas resistant to other dopamine agonists have been shown to respond to cabergoline (11, 12). In a recent large retrospective study of 452 patients with pathological hyperprolactinemia, most of whom had pituitary tumors, cabergoline was shown to be effective in many patients who were previously bromocriptine intolerant or resistant (13). Our current practice is to treat most patients who do not wish to become pregnant with cabergoline. Women who wish to become pregnant are still treated initially with bromocriptine because of the extensive safety record with bromocriptine for this purpose. A growing number of women, however, have become pregnant while taking cabergoline and have delivered healthy children, but the numbers are still relatively small. It is anticipated that in the future cabergoline may be recommended as the drug of choice for this purpose as safety data accumulates. Once pregnancy is confirmed, bromocriptine is usually stopped. Women with microadenomas are very unlikely (<5%) to experience problems with clinically significant tumor growth during pregnancy (14). With macroadenomas, however, it is more likely (15–35%) that the tumor will re-expand after bromocriptine withdrawal and may enlarge further, causing compressive symptoms with continued estrogen stimulation during the course of pregnancy. If the patient becomes symptomatic, bromocriptine can be restarted or surgery can be considered. In all patients, when initiating therapy with any of the dopamine agonist drugs, it is important to start with a very small dose to minimize side effects. The most common side effects are nausea, vomiting, and postural hypotension. These side effects usually disappear with continued treatment. With bromocriptine and pergolide it is our practice to begin with a quarter to half tablet once a day with a snack at bedtime. The dose is then gradually increased as tolerated by the patient to 2.5 mg po twice or three times a day for bromocriptine and 0.05–0.1 mg po daily for pergolide. Cabergoline is started at a dose of mg po once a and gradually increased to mg once or twice a A serum PRL is after and if the dose can be agonists be considered the of even with very large invasive PRL-secreting tumors that are causing compressive Medical therapy often causes tumor shrinkage in these patients, and the majority require If is visual and visual fields be carefully monitored. PRL levels also be and the dose of dopamine agonist be In if the PRL not it is unlikely that will be significant tumor shrinkage. A in however, is not always by tumor shrinkage. It important to tumor shrinkage by a MRI in or if is and not In many patients, visual may as the tumor In some patients with visual however, may not tumor shrinkage and of the optic chiasm. In these patients it is unlikely that will with If the optic is not however, surgery may be indicated to restore The majority of patients with large prolactinomas, however, can be treated with dopamine agonists and require Once PRL levels and has been significant tumor it is very unlikely that the patient will become resistant to drug therapy. It is not for the dopamine agonist dose to be during long-term treatment. the of untreated PRL-secreting microadenomas is quite for treatment on the agonist treatment will the hypogonadism and restore fertility in most estrogen therapy can be used to treat symptoms of estrogen and to prevent the long-term of estrogen can be used to treat women who Treatment with estrogen without treatment with dopamine agonists to be safe and not to be with significant tumor growth in most Patients be however, and PRL levels be because is a small that estrogen tumor growth. If tumor growth is noted while taking therapy with a dopamine agonist be In the majority of patients with PRL-secreting microadenomas and macroadenomas can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective for patients who are resistant to or intolerant of these GH-secreting pituitary tumors to of pituitary tumors for surgical therapy These tumors, are the etiology of in all present after of symptoms that in tissue and symptoms in some of pituitary tumor mass effect such as visual or Once is by the of an of of after and a pituitary mass on will be by elevated levels, but a not the Very rarely, can and be considered and in patients with of but absence of a pituitary mass on MRI The of therapy for are to normalize the excess secretion of growth hormone and the symptoms and to or large tumors to prevent damage to parasellar excess secretion in is with a greater than in the and an increased due to the and sleep and of this that the increased with can be to normal with therapy that the and levels the of therapy be to as by a normal and by a after of less than ng/mL by a sensitive Transsphenoidal surgery, with in many patients and very is to be the of therapy for most patients with In recent experienced pituitary of microadenomas and half of macroadenomas will on of levels after transsphenoidal surgery two of macroadenomas can be The recurrence after defined cure is quite at less than after transsphenoidal surgery occur in less than of and of secretion of and or patients who do not after transsphenoidal surgery, available therapeutic medical therapy with dopamine agonists and therapy. data that radiotherapy may not be as effective in curing as previously if of is used to Several recent have that a in levels in most patients, only of patients will of after radiotherapy such as and are of can be with the of effective medical and the of radiotherapy the to therapeutic effect and high to of with usually radiotherapy for large or invasive macroadenomas that not be or for patients resistant to medical therapy. Medical therapy has a more in the treatment of as the numbers and of the available have The two of available in the United States for therapy of are dopamine agonists and Although many treated with the dopamine agonist bromocriptine will have some in symptoms, only of patients will a less than ng/mL and will normalize in only Bromocriptine is often required in large doses to and side effects are the more dopamine agonist, approved in the United States for use in PRL-secreting tumors, for improved and bromocriptine for the treatment of In a recent study, in patients with treated with cabergoline at doses for to a levels in of patients and to in another or levels were with a tumors that PRL are more likely to be to cabergoline therapy. with other dopamine the most side effects are nausea, and but in studies with bromocriptine in patients with prolactinomas the side effects have been less with cabergoline (10). In patients with to after surgery, and who are symptomatic, a of a dopamine agonist such as cabergoline be considered. Cabergoline is at a dose of and can be increased as tolerated to as to normalize levels. The most effective medical for available are the of the are now available in the United States for treatment of a and a long-acting The of is as three daily of also can be a with a greater are not to effectiveness The long-acting in the United is administered as a in doses 10 mg to mg is the recommended patients to these an of the of be administered to drug the clinical have shown of and levels in patients the to the of of levels can be to occur in of patients treated with for to and to of patients will of levels with the Although only a small of patients who to the had a more response to the in clinical the improved with the may in a greater in clinical practice with this Although and levels do not normalize in to one of patients treated with symptomatic can be in most and in is in to of of improved with treatment the that effective medical therapy may on and in to the use of these in some patients with is that long-term data on tumor shrinkage with use is only of patients treated with a significant in tumor size shrinkage data with the is available in only a very small number of are not with and in most patients with continued Although to of patients will during they in the majority of patients and be as in patients In patients, during is not to be less side effects of function, and and also at the of in a small of patients the and dopamine agonist therapy may also additional The longer-acting of because of of likely will be as the therapy of choice in most patients who surgery for The may be in such as for treatment in patients with of or significant cardiovascular to to lower levels and reduce In in the of surgical cure is or in whom surgery is the have been as therapy for of such patients will be to with to tumor size in with patients transsphenoidal In the of that at the receptor as antagonists may also the of drugs available for the treatment of data clinical with a that this is well tolerated and in doses levels in all patients with including resistant to In transsphenoidal surgery is the primary treatment of choice in the majority of patients with The of primary medical therapy with in patients unlikely to be is to be patients with of or levels after surgery, medical therapy be patients with disease, a of the dopamine agonist cabergoline can be If this or in patients with to disease, therapy with a be In the the may also be another for medical therapy. in with medical be considered for patients with significant tumor after surgery or in whom medical therapy is Patients with pituitary tumors, Cushing’s disease, usually present with clinical of These and In addition, excess of in women is with and Cushing’s times more frequently in women than in men, with the of Cushing’s be other causes of Cushing’s tumors and secretion of ACTH by a as well as The diagnosis of Cushing’s is usually on the of the clinical and data than by the of the pituitary tumor. of the small size of these tumors, are not by MRI with enhancement. It be that because a number of microadenomas in the these techniques are only helpful once a clinical and diagnosis of Cushing’s has been and and levels are helpful in a diagnosis of Cushing’s ACTH levels, and stimulation can then be used to the cause of Cushing’s The majority of patients with Cushing’s have ACTH levels in the high normal but elevated for the of In patients with tumors have ACTH levels that do not respond to stimulation with Once a diagnosis of Cushing’s has been it is important to Cushing’s ACTH Patients with ACTH may have extremely elevated ACTH levels, but often is with the ACTH levels in Cushing’s disease. can be helpful in that most patients with Cushing’s respond to with a in ACTH and levels, patients with ACTH secretion usually do not respond to The most reliable however, to pituitary ACTH secretion is by sinus can be used to measure ACTH levels in the venous blood draining the pituitary sinus sampling in with stimulation when the MRI is studies are This also has been in some to be for of pituitary for the in a if is Transsphenoidal surgery is the treatment of choice for patients with Cushing’s disease. are usually in most patients at the of surgery and can be with of normal If is a by the sinus ACTH levels may be in an patient in whom fertility is not an a may be because of the and with this disease. In large of patients transsphenoidal surgery for Cushing’s disease, cure rates of have been for tumors to the patients have been by but a small number have been by if tumor was at In a large by was an of in patients after transsphenoidal In that of patients had recurrence of disease. 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The only side effect noted in this was the development of of in of of radiotherapy or the may to be very but long-term with these techniques for pituitary tumors is Medical therapy is usually required to lower levels while for the radiotherapy to Medical therapy for Cushing’s is primarily at the and of of an that at has been shown to levels in patients with Cushing’s and inhibition of the also The dose is usually mg administered but doses of to may be The major side effects are in function and function be during therapy. high doses may If is not effective or well other including and can be doses of drugs can be used in to minimize side effects. an related to has been used to lower levels in patients who a receptor has been used in a small number of patients, but it is to effectiveness other than by the clinical response because levels will not and may actually Medical therapy is not considered primary therapy for Cushing’s disease, but is often used in with radiotherapy or in a very patient to the clinical was the treatment in the is still used in patients who surgery and but treatment with and will be In addition, patients are at for by a in due to an in ACTH levels and pituitary tumor growth. The is however, by pituitary In the majority of patients with Cushing’s can be by transsphenoidal surgery with with of normal Patients will require and during the of that the If surgery a more extensive surgical radiotherapy is Medical therapy with and other can be used as therapy to lower levels. tumors are very less than of pituitary These tumors may present with symptoms of a and of a pituitary mass The major differential diagnosis to when patients with function of a pituitary tumor is the of hormone In but not all the of response to of serum and high with a pituitary mass on MRI are of these pituitary tumors be treated initially one of these tumors will be by surgery because most are macroadenomas, to be invasive at is recommended as therapy when surgery has not been after surgery and radiotherapy only two of tumors will be is very with dopamine agonists for treatment of these tumors. With however, can be controlled in most levels have been to normalize in of patients, and tumor shrinkage can occur in of patients treated with and tumors that present with clinical symptoms of hormone hypersecretion are very Thus, the majority of tumors are clinically Pituitary tumors that present without clinical and of pituitary hormone hypersecretion are clinically and are in the majority of of Although clinically in that most of these tumors do hormones or including or less are usually but elevations of or may be in some patients Some have of to be a as well as an in or levels after stimulation tumors, usually macroadenomas, to medical because of visual symptoms of or These tumors need to be other masses that can a pituitary The major in the differential diagnosis of pituitary are tumors to the and and is very at in pituitary and consideration of a lesion. Although clinical and may in the diagnosis of some will not be the of surgery tumors may be by modest hyperprolactinemia, usually less than 100 due to compression of the pituitary The of pituitary macroadenomas is transsphenoidal surgery with the of tumor mass and of parasellar Transsphenoidal surgery has a in in visual in many and may lead to of pituitary of the large size and parasellar in many of these tumors, they often be after recurrence rates after surgery may be as high as radiotherapy is an for treatment of tumor. However, data on the and of radiotherapy for tumors are not The to to radiotherapy after surgery on the size of the the and the to pituitary radiotherapy is clearly not in may to with scans for the and then to the of growth of the tumor and radiotherapy if is tumor growth. at medical therapy of pituitary tumors with dopamine agonists and of have with in because only a of these tumors dopamine or In a bromocriptine therapy has decreased tumor but tumor shrinkage not occur in most use of has been in in some patients with these tumors but the response is very and use be as with bromocriptine for patients to other pituitary tumors are not on imaging studies for in patients without symptoms to the pituitary tumor. The of these tumors or is microadenomas need not be treated and can be with however, that surgery be considered for macroadenomas. on the size of the tumor and other medical conditions, however, one may to the tumor on pituitary imaging studies and clinical and pituitary however, is actually available on the of pituitary tumors. are to have safe and effective therapeutic available for the treatment of pituitary tumors. These medical transsphenoidal surgery and The treatment of choice on the of pituitary tumor. The majority of PRL-secreting tumors can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective for patients who are resistant to or intolerant of these Transsphenoidal surgery remains the treatment of choice for the majority of patients with and tumors and for large tumors. Medical therapy with dopamine agonists be in patients with elevations of and radiotherapy be considered for patients with significant tumor in whom medical therapy is is also indicated for tumors not by medical therapy with and other can be used as therapy to lower levels. radiotherapy for tumors is also an if is tumor or of tumor growth on and treatment of is an important of the of all patients with pituitary tumors. Patients also be for the development of after The development of medical such as as well as of and imaging techniques continue to our of pituitary tumors.
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Freda et al. (1999) studied this question.