Management of Pituitary Tumors

Methods

The MEDLINE database was searched to identify relevant English-language literature published in the past 15 years, including controlled clinical trials, large series of treated pituitary adenomas, and review articles and book chapters. The major sources of information for this review were articles published in major clinical, peer-reviewed, general medicine and endocrinology journals in the past 8 years. We also used a personal pituitary database, collected since 1980, and augmented this information by searching reference lists in identified publications to locate previously published data.

Prolactin-Secreting Adenomas

Prolactinomas, the most common hormone-secreting pituitary adenomas, make up approximately 60% of functioning tumors [1]. In hyperprolactinemic women, microadenomas with lower prolactin levels predominate; these patients present with amenorrhea, infertility, and galactorrhea. Men usually have macroadenomas with higher prolactin levels and present with impotence, loss of libido, or infertility. The hypogonadal state associated with hyperprolactinemia may also result in osteoporosis. The natural history of untreated hyperprolactinemia in women is usually stable, and these patients are unlikely to have disease progression [2]. Once a microprolactinoma is detected, only about 5% of patients will develop macroadenomas [1].

Since the clinical introduction of bromocriptine more than 25 years ago [3, 4], medical therapy has become the preferred treatment for prolactinomas [5]; transsphenoidal surgery is less successful (Table 1). About 70% of microprolactinomas and only 30% of macroprolactinomas are initially cured (evidenced by normalization of prolactin levels) after surgery [1]. Moreover, early recurrence of hyperprolactinemia (within the first year after surgery) occurs in 15% to 20% of cases, whereas rates of long-term recurrence of macroadenoma may exceed 50% [6]. Radiation treatment has a limited effect in patients with prolactinomas. Thus, a dopamine agonist (cabergoline or bromocriptine) should be the initial therapy in patients with either microprolactinomas or macroprolactinomas (Figure 1). These patients must be monitored carefully by measurement of serum prolactin levels, pituitary magnetic resonance imaging, and visual field examinations. Surgery may be necessary in hyperprolactinemic patients intolerant of or resistant to dopamine agonists and patients with invasive macroadenomas and compromised vision with no immediate response to medical treatment (Figure 1). Even this surgical debulking is rarely curative, however, and dopamine agonist treatment is usually required after surgery to control the hyperprolactinemia. Because the risk for microprolactinoma progression to macroadenoma is minimal, low-dose estrogens can be used to prevent osteoporosis if the patient does not desire fertility. Although there is little risk for enlargement of pituitary tumors with low-dose estrogens, no definitive published study has documented this. Patients should be monitored by regular, serial measurement of prolactin.

Bromocriptine

Bromocriptine mesylate is a semisynthetic ergot alkaloid and a long-acting dopamine receptor agonist [7]. It suppresses prolactin secretion by directly binding to D2 dopamine receptors within the anterior pituitary. Dopamine agonists inhibit secretion and synthesis of prolactin and proliferation of lactotroph cells in the anterior pituitary [8]. Bromocriptine is indicated as initial therapy for both microprolactinomas and macroprolactinomas (Figure 1) in men and women. Bromocriptine has been successful in 80% to 90% of patients with microadenomas, rapidly decreasing serum prolactin levels to normal, decreasing the tumor size, and restoring normal gonadal function [7, 9]. Normalized prolactin levels and tumor shrinkage (by ≥ 50%) occur in 60% to 75% of patients with macroprolactinomas treated with bromocriptine [7, 10-12], and abnormal visual fields improve in most patients [7, 10]. Symptoms of mass effect, including headaches and visual disorders, usually improve dramatically within days after initiation of bromocriptine treatment [13]. Sexual function may improve even before complete normalization of prolactin levels.

Although prolactinoma cells usually remain sensitive to bromocriptine, the drug does not “cure” these adenomas, and discontinuation of therapy often results in recurrent hyperprolactinemia [14-16]. Tumor reexpansion may occur later, with the consequent risk for compromised vision. Thus, titration of the bromocriptine dose to the lowest effective maintenance level is recommended after the tumor has initially been controlled [11]. However, in a small subgroup of treated patients, usually those with small microadenomas, hyperprolactinemia may resolve and prolactin levels may remain normal when long-term bromocriptine therapy is discontinued [17].

Continued bromocriptine treatment is associated with increased fibrosis of prolactin-secreting tumors [18, 19] and with increasing tumor consistency. Resistance to dopaminergic treatment and persistent tumor growth occur in some patients [14]; these may be associated with decreased D2 dopamine receptors or a postreceptor defect [20] but are not associated with mutations in the D2 dopamine receptor gene [21]. Recently, in vivo imaging of macroprolactinomas done by using a radiolabeled D2 dopamine receptor radioligand has been used to predict the prolactin response to dopamine agonist treatment [22].

After the initial dose, nausea, vomiting, and postural hypotension with faintness occur in some patients [23]. Therapy should be started at night with 0.625 to 1.25 mg of bromocriptine consumed with a snack; the dose should then be gradually increased. Most patients are successfully treated with 7.5 mg of bromocriptine (2.5 mg three times daily) or less. Other side effects, such as nasal stuffiness, psychosis, hallucinations, nightmares, insomnia, and vertigo, can be reversed after the drug dose is decreased. Approximately 5% of patients do not tolerate oral bromocriptine. Bromocriptine administration during pregnancy is not approved by the U.S. Food and Drug Administration (FDA).

To overcome the short duration of action of oral bromocriptine and its possible hepatic first-pass effect, a parenteral long-acting form of bromocriptine (not available in the United States) was developed for weekly intramuscular injections given four times a week (50 to 100 mg per injection) [24]. In this preparation, bromocriptine is incorporated into biodegradable microspheres. In patients with macroprolactinomas, results similar to those seen with oral bromocriptine were achieved [25, 26]. Nausea and postural hypotension developed after the first injection but rarely occurred 24 hours after the first dose [25].

Hyperprolactinemic women intolerant of oral bromocriptine may respond well to intravaginal bromocriptine (a 2.5-mg tablet once daily), with accompanying normalization of prolactin levels, adenoma shrinkage, and fewer gastrointestinal side effects [27, 28].

Cabergoline

Cabergoline, an ergoline derivative dopamine agonist with specificity for the D2 receptor and a very prolonged duration of action, effectively suppresses prolactin for more than 14 days after a single oral dose and induces tumor shrinkage in most prolactinomas studied [29]. In the largest double-blind comparison of bromocriptine with an alternative dopamine agonist, Webster and colleagues [30] treated 459 women who had hyperprolactinemic amenorrhoea (macroadenomas were not included) with either bromocriptine (2.5 to 5 mg twice daily) or cabergoline (0.5 to 1.0 mg twice weekly). Cabergoline was significantly more potent in achieving normoprolactinemia (83% of patients compared with 59%) and resumption of normal gonadal function (72% of patients compared with 52%). Galactorrhea disappeared in 90% of patients treated with cabergoline and in 78% of those treated with bromocriptine. Adverse effects and drug intolerance were less common in the cabergoline group. However, the relatively low efficacy of bromocriptine reported in this study is surprising and not well explained. Recently, cabergoline was reported to normalize prolactin levels and shrink 73% of macroprolactinomas [31]. Cabergoline may also be effective in patients resistant to bromocriptine [32].

Pergolide Mesylate

Pergolide mesylate, an ergot derivative with dopaminergic properties, has a duration of action of more than 24 hours. A single daily oral dose of 200 µg normalizes prolactin levels in most patients with hyperprolactinemia and results in tumor shrinkage in two thirds of patients [33]. Side effects are similar to those of bromocriptine. However, the FDA has not approved pergolide for treatment of prolactinomas.

Lisuride

Lisuride, an ergot derivative dopamine agonist that is equally effective in suppressing prolactin and reducing tumor size at a dosage of 0.4 to 2 mg/d [34], has several side effects (nausea, dizziness, and depression) that limit its use [35]. This drug has not been approved by the FDA for treatment of prolactinomas.

Quinagolide

Quinagolide is an octahydrobenzyl(g)-quinoline nonergot oral dopamine agonist with specific D2 receptor activity. It has a prolonged suppressive effect on serum prolactin when given once daily [36], and dosages of 0.1 to 0.5 mg/d suppress prolactin to normal levels in 60% of patients with macroprolactinomas. The drug also decreases tumor size and restores normal gonadal function in most patients [37]. This preparation (not approved by the FDA for treatment of prolactinomas) produces side effects that are similar to those of bromocriptine [38] and may lead to normal prolactin levels in half of bromocriptine-resistant prolactinomas [39].

Somatostatin Analogues

Prolactin-secreting pituitary adenomas express somatostatin receptor subtypes 1, 2, 3, and 5 [40-42]. In patients with prolactinoma, somatostatin and octreotide, which bind preferentially to somatostatin receptor 2, do not alter in vivo prolactin levels [43, 44]. However, by use of novel somatostatin receptor 5-selective somatostatin analogues, prolactin secretion has been suppressed in cultures of human lactotroph adenomas [45]. Thus, these compounds may be effective in the treatment of prolactin-secreting pituitary adenomas.

Summary

Effective medical treatment with dopamine agonists is the preferred therapy for prolactinomas. Surgery is infrequently required for resistant tumors.

Growth Hormone-Secreting Adenomas

Somatotroph adenomas that secrete growth hormone account for 20% of functional pituitary tumors. Seventy-five percent of these benign tumors are macroadenomas [46], and many present with parasellar or suprasellar invasion. Because symptoms of acromegaly progress slowly, diagnosis may be delayed 7 to 10 years [47]. Acral and soft-tissue overgrowth occur in almost all patients with acromegaly. These characteristic signs, accompanied by generalized visceromegaly, arthropathy, the carpal tunnel syndrome, muscle weakness, and hyperhydrosis, cause chronic pain, discomfort, and disfigurement. Pituitary tumor mass effects, including headaches, hypopituitarism, and visual disturbances, are common. Furthermore, the increased frequency of cardiovascular disease, hypertension, diabetes, upper-airway obstruction and sleep apnea, and gastrointestinal cancer [48] shortens life expectancy, leading to overall mortality rates that are about two to three times higher than those in age-matched controls [47, 49]. Remarkably, aggressive medical intervention may decrease mortality rates, even when clinical and biochemical disturbances are mild [50].

Growth hormone-secreting adenomas should be resected surgically. Somatostatin analogues may be used as adjuvant therapy or as primary treatment in selected cases, including presurgical therapy in patients with large invasive macroadenomas (Figure 2), immediate relief of symptoms and reduction of growth hormone hypersecretion in patients awaiting surgery or those with recurrent disease, morbidity in elderly patients, and a patient's decision not to undergo surgery. Treatment with somatostatin analogues or bromocriptine should also be initiated when previous surgical therapy has not achieved biochemical remission [51]. Patients who are resistant to medical management should be referred for sellar irradiation or additional surgery. The high rate of late hypopituitarism and slow response rate (5 to 10 years) are the main disadvantages of conventional radiation therapy in acromegaly. Moreover, a recent study has shown the ineffectiveness of pituitary irradiation in normalizing insulin-like growth factor-I (IGF-I) levels in acromegalic patients despite the low random growth hormone levels achieved [52]. However, although stereotactic ablation of growth hormone-secreting adenomas by γ-knife radiosurgery is promising, long-term results are not yet available.

Surgery

Transsphenoidal surgery performed by a skilled neurosurgeon is the preferred primary treatment for both microadenomas and macroadenomas (cure rates, approximately 70% and approximately 50%, respectively) [53, 54] (Figure 2; Table 1). Symptoms of soft-tissue swelling start improving immediately after successful tumor resection. Growth hormone levels usually return to normal within 1 hour, and IGF-I levels become normal after 1 week. Residual pituitary function is usually preserved after resection of well-encapsulated tumors, and signs of preoperative tumor compression are often restored by surgery. However, acromegaly may recur several years after surgery in 5% to 10% of patients who have had the operation, and pituitary failure is found in up to 15% of patients.

Octreotide

Octreotide acetate, an eight-amino acid, long-acting synthetic somatostatin analogue, was introduced as an effective therapy for acromegaly more than a decade ago [55]. This advance allowed acromegaly to be controlled by a drug, even without previous surgery or radiation therapy. The analogue has a plasma half-life of 2 hours after subcutaneous injection and a potency at least 40-fold greater than that of somatostatin for suppression of growth hormone; this effect is exerted through somatostatin receptors 2 and 5 [56], which are expressed by growth hormone-secreting tumors [40-42]. The drug is administered in three daily injections (≥ 50 µg each), and the dose can be gradually increased to as high as 1500 µg. Some patients respond satisfactorily to the lowest dose, whereas others exhibit only partial suppression with maximal doses. Growth hormone inhibition by a test dose of octreotide correlates directly with the presence of somatostatin receptor subtypes on radiolabeled octreotide scanning [57]; this inhibition also predicts long-term octreotide response.

In most patients with acromegaly, a subcutaneous injection of 100 µg of octreotide suppresses growth hormone secretion to 20% to 30% of baseline within 1 hour, an effect that lasts 4 to 6 hours [58]. Less than 10% of treated patients have no response to the analogue [59]. Within 5 hours after injection, octreotide administered every 8 hours suppresses integrated growth hormone levels to less than 5 µg/L in 50% of patients with acromegaly and to less than 2 µg/L in 25% of patients [58] and normalizes IGF-I levels in 47% of patients [58, 59]. The drug is less effective in patients with macroadenomas, normalizing IGF-I levels in 43% of patients; in 82% of patients treated for microadenomas, however, elevated IGF-I levels returned to normal [58]. Improved results were recently reported in 103 patients during long-term octreotide treatment (mean duration of treatment, 24 months); growth hormone levels 2 hours after injection were suppressed to less than 5 µg/L in 65% of patients and to 2 µg/L or less in 40% of patients [60]. Fifty-six percent of patients with elevated IGF-I levels at baseline had normalization of these levels during treatment [60]. In up to 75% of all patients treated, headache and soft-tissue swelling were quickly relieved (within days to several weeks after treatment initiation) [58, 59]. Subjective clinical benefits of octreotide therapy are greater than the biochemical remission (that is, growth hormone level < 2 µg/L after glucose suppression and normalization of IGF-I levels), evidenced by the fact that up to 95% of patients report symptom improvement [60]. Tumor size is significantly reduced in about 40% of patients within several months [58, 59], but this effect is reversible if treatment is stopped [58]. Prolonged use of the analogue is not associated with desensitization, even after 10 years of treatment.

One quarter of patients with acromegaly have clinical diabetes. Octreotide therapy leads to enhanced insulin sensitivity and a dramatic decrease in the insulin requirement of diabetic patients. Acromegaly is associated with left ventricular hypertrophy, diastolic dysfunction, ischemic heart disease, and hypertension. Octreotide treatment does not cure hypertension, but biochemical remission is associated with a rapid decrease in left ventricular mass [61]. Upper-airway obstruction and sleep apnea are common in patients with acromegaly, and octreotide frequently improves indices of sleep apnea severity [62].

Octreotide is well tolerated in most patients. Most adverse effects are short-lived and relate to drug-induced suppression of gastrointestinal motility and secretion [63]. These effects, occurring in one third of patients, include nausea, abdominal discomfort, fat malabsorption, diarrhea, and flatulence and usually remit within 2 weeks [60]. The most significant side effect involves the gallbladder. Octreotide attenuates postprandial gallbladder contractility and delays gallbladder emptying, and up to 30% of U.S. patients receiving long-term treatment develop asymptomatic cholesterol gallstones or echogenic sludge [58, 60]. Other side effects include mild glucose intolerance due to transient suppression of insulin secretion, asymptomatic bradycardia, depression, hypothyroxinemia, and local pain at the injection site. Continued treatment rarely results in development of specific antibodies against octreotide [64], which may significantly prolong the plasma half-life of octreotide and, consequently, the interval of maximum growth hormone inhibition.

A sustained-release, long-acting formulation of octreotide (not approved by the FDA) incorporated in microspheres produces sustained elevated levels of octreotide in contrast to the peaks and troughs seen with subcutaneous octreotide administration. Similar growth hormone suppression occurs in patients with acromegaly for as long as 6 weeks after a single 30-mg intramuscular injection of this preparation [65, 66]. Long-term treatment leads to stable and consistent suppression of growth hormone and IGF-I levels [67] and reduces the size of pituitary tumors.

Lanreotide

Lanreotide (not approved by the FDA for treatment of growth hormone-secreting tumors), a long-acting, slow-release depot somatostatin preparation, is a cyclic octapeptide analogue of somatostatin that suppresses hypersecretion of growth hormone and IGF-I in patients with acromegaly for 10 to 14 days after a 30-mg intramuscular injection [68, 69]. The long-term administration of this drug controls acromegaly in two thirds of treated patients [70], an effect similar to that achieved by octreotide. Patient compliance is better with lanreotide than with octreotide because of the long interval between injections of the former. Tumors significantly shrink in about 15% of patients [69, 70]. The most frequent side effects of lanreotide include transient abdominal pain and diarrhea after initiation of therapy and asymptomatic gallstones.

These long-acting formulations are effective and well tolerated and are associated with less patient inconvenience than the current subcutaneous octreotide regimen. They will probably be the future medical treatment of choice for acromegaly.

Dopamine Agonists

Bromocriptine may suppress growth hormone secretion in patients with acromegaly but may lead to acute growth hormone release in healthy persons. Before octreotide was introduced, bromocriptine was commonly used as effective therapy for acromegaly. Acromegalic patients usually require 20 mg/d or more to suppress growth hormone, a dosage greater than that required to normalize prolactin levels in patients with prolactinoma. Moreover, instead of the two daily doses required to suppress hyperprolactinemia, three to four daily doses are needed to suppress growth hormone secretion in acromegaly. The therapeutic efficacy of bromocriptine reported in 549 patients with acromegaly from 31 different clinical studies is lower than that of octreotide [71]. Bromocriptine suppressed random growth hormone levels to less than 10 µg/L in 53% of patients and to less than 5 µg/L in 20% of patients [71]. Levels of IGF-I return to normal in only 10% of treated patients, and less than 20% of growth hormone-secreting tumors shrink [71]. Most patients experience subjective clinical improvement while taking bromocriptine, with no correlation to growth hormone or IGF-I levels. Cabergoline did not normalize growth hormone or IGF-I levels in 11 patients with growth hormone-cell tumors treated with 1 mg twice a week [72], but it did suppress growth hormone and decrease adenoma size when 0.5 mg/d was given [73]. Quinagolide (0.3 to 0.6 mg/d) suppressed growth hormone and IGF-I levels to normal in about 30% of treated patients [72].

Combined treatment with octreotide and bromocriptine induces an additive suppressive effect on growth hormone and IGF-I in patients with acromegaly compared with treatment with either drug alone [74, 75]. The bioactivity of bromocriptine increases when bromocriptine is administered together with octreotide [75].

Growth Hormone Antagonists

Growth hormone analogues that antagonize endogenous growth hormone action at the peripheral receptor binding site of growth hormone [76, 77] and growth hormone-releasing hormone antagonists that block the effects of this hormone in the hypothalamus and pituitary and suppress serum growth hormone and IGF-I [78, 79] may prevent secretion of growth hormone and IGF-I in patients with acromegaly.

Summary

Surgery is the preferred primary treatment for growth hormone-secreting microadenomas. The high persistence rate of growth hormone hypersecretion after macroadenoma resection usually necessitates adjuvant, or primary, medical therapy for these larger tumors [51]. Patients resistant to medical treatment are offered radiation.

Adrenocorticotropin-Secreting Adenomas

Most adrenocorticotropin hormone (ACTH)-producing tumors (90%) are microadenomas; these tumors make up 15% of functional pituitary adenomas. The current treatment of choice for Cushing disease is selective transsphenoidal adenomectomy after accurate preoperative localization of the corticotroph adenoma (Figure 3). The cure rate of this procedure is about 80% to 90% for microadenomas [80] but only up to 50% for macroadenomas. Hypopituitarism associated with permanent hypocortisolism may occur. In most cured patients, a postoperative period of adrenal insufficiency lasts as long as 6 months. Hypercortisolism recurs in approximately 5% of patients who have had successful surgery by experienced neurosurgeons.

Patients whose condition is not controlled by surgery are referred for pituitary irradiation, which may cure up to 15% of patients after several years. Irradiation may be combined with medical treatment to achieve early biochemical remission of hypercortisolism, even before the effects of irradiation become established. The development of effective alternative pharmacotherapy for the Cushing syndrome (cortisol-decreasing agents) has significantly decreased the need for bilateral adrenalectomy, a procedure associated with substantial morbidity and mortality, requirement for permanent hormone replacement therapy, and subsequent risk for development of the Nelson syndrome. However, drug therapy is rarely used alone to treat Cushing disease; it is usually an adjuvant therapy.

Steroidogenic Inhibitors

Mitotane

The adrenolytic agent o, p′-DDD (mitotane) suppresses cortisol hypersecretion by inhibiting 11 β-hydroxylase and cholesterol side-chain cleavage enzymes and destroying adrenocortical cells. Mitotane (an enteric coated preparation, 12 g/d) achieves remission in 83% of patients after 8 months of therapy [81]. Combined treatment with mitotane and pituitary irradiation results in biochemical remission in 80% to 100% of patients after 8 to 16 months [81, 82]. However, after discontinuation of mitotane therapy, sustained remission rates decrease to about 50% to 70% [81, 82]. Mitotane use is associated with gastrointestinal distress, neurologic side effects, gynecomastia, hyperlipidemia, skin rash, and elevated hepatic enzyme levels. It may also lead to hypoaldosteronism.

Ketoconazole and Etomidate

Ketoconazole, an imidazole-derivative antimycotic agent, inhibits various cytochrome p450 enzymes, including the side-chain cleavage complex; 17,20-lyase; 11 β-hydroxylase; and 17 α-hydroxylase. Ketoconazole (600 to 800 mg/d administered twice daily) is highly effective in decreasing cortisol levels in most patients with Cushing disease [83]. Adrenocorticotropin hormone is not suppressed; however, because plasma ACTH levels do not increase while patients are receiving therapy (despite reduction of the cortisol feedback), it has been suggested that the drug has independent effects on ACTH secretion. Elevated hepatic aminotransferase levels, gynecomastia in men, gastrointestinal upset, and edema are commonly reported side effects [83]. Another imidazole derivative, the anesthetic drug etomidate (not approved by the FDA for treatment of ACTH-secreting tumors), also suppresses cortisol synthesis. When given intravenously at a nonhypnotic dose (0.3 mg/kg of body weight per hour), it has an immediate cortisol-lowering effect [84].

Metyrapone

Metyrapone (2 to 4 g/d) primarily inhibits 11 β-hydroxylase activity and normalizes plasma cortisol levels in 50% to 75% of patients with Cushing disease [85]. Side effects include severe nausea and vomiting, exacerbation of acne or hirsutism, and development of central nervous system symptoms.

Aminoglutethimide

This anticonvulsant drug inhibits several cytochrome p450 steroidogenic enzymes. Less than 50% of patients with Cushing disease respond to treatment with aminoglutethimide (250 mg three times daily) [86]. The combination of this drug with pituitary irradiation is highly effective in most patients with Cushing disease. Aminoglutethimide may cause sedation, nausea, rash, and goiter.

Trilostane, a carbonitrile derivative, inhibits conversion of pregnenolone to progesterone. At 200 to 1000 mg/d, this drug decreases cortisol production and has side effects similar to those seen with aminoglutethimide (not approved by the FDA) [83].

Neuromodulators of Pituitary Secretion of Adrenocorticotropin Hormone

Octreotide has no beneficial clinical role in normalization of ACTH or cortisol levels in patients with Cushing disease [83]. Less than 10% of patients with Cushing disease seem to modestly respond to long-term bromocriptine therapy with normalization of urine and plasma levels of glucocorticoids and suppression of ACTH [83]. Cyproheptadine (24 mg/d), an antiserotonergic and antihistamine agent, may suppress ACTH and cortisol secretion in some patients with Cushing disease [83]. Cyproheptadine can cause somnolence, hyperphagia, and weight gain.

Summary

Transsphenoidal surgery should be the primary therapy in the management of Cushing disease. Cortisol-decreasing drugs are reserved for patients in whom surgery has not cured the disease and is usually given with pituitary irradiation to block peripheral (adrenal) effects of high ACTH levels. Mitotane therapy combined with irradiation is the preferred treatment after surgical failure; it is usually used for months until the delayed biochemical clinical improvement induced by irradiation occurs. Aminoglutethimide or metyrapone can also be added to mitotane to improve the success rate, and the combination of metyrapone and aminoglutethimide is also effective.

Thyroid-Stimulating Hormone-Secreting Adenomas

Thyroid-stimulating hormone (TSH)-secreting adenoma is a rare disorder (0.5% to 1% of all pituitary adenomas) that results in secondary (central) hyperthyroxinemia and goiter. More than 70% of these tumors are macroadenomas [87]. The initial therapeutic approach should be to surgically remove or debulk the tumor mass. Because many of these tumors are large and locally invasive, complete resection, either by the transsphenoidal or subfrontal approach, may be dangerous and impractical. About two thirds of patients with TSH-secreting adenomas have normal circulating thyroid hormone levels after surgery alone or surgery combined with radiation therapy [87], but only one third of these patients are considered cured. Thyroid ablation or antithyroid drug treatments (methimazole or propylthiouracil) do not improve the results of surgery or radiation therapy. Moreover, these treatments may infrequently increase tumor growth and aggressiveness by releasing the thyrotroph cell from thyroid feedback inhibition. Dopamine agonists are not effective in suppressing TSH secretion from these tumors.

Octreotide (50 to 750 µg delivered subcutaneously two to three times daily) reduces TSH and α-subunit hypersecretion to less than 50% of basal levels in more than 90% of patients; TSH levels return to normal in up to 80% of patients, tumor mass shrinks in 50%, vision improves in 75%, and euthyroidism is restored in most patients [87-89]. In some patients, octreotide treatment results in marked TSH suppression and biochemical hypothyroidism, requiring concomitant thyroid hormone replacement therapy. Thyroid hormone and TSH levels are usually controlled with octreotide doses lower than those required to suppress growth hormone in patients with acromegaly [89]. Recently, the long-acting, slow-release somatostatin analogue lanreotide effectively suppressed TSH and thyroid hormone levels to normal levels in patients with TSH-secreting adenomas treated every 14 days (30-mg intramuscular injections) for several months [90]. Thus, somatostatin analogue treatment is effective for TSH-secreting pituitary adenomas when surgery and radiation therapy do not cure these rare tumors.

Nonfunctioning Pituitary Adenomas

Clinically nonfunctioning pituitary adenomas, also called gonadotroph-cell adenomas, make up about one third of all pituitary tumors and are the most common macroadenomas. Although the gonadotroph cells give rise to these tumors, most secrete gonadotropins inefficiently while their subunits (α-subunits, follicle-stimulating hormone-β subunits, and, rarely, luteinizing hormone-β) are often discordantly secreted. The presentation of these tumors is often determined by their local mass effects, including optic chiasm pressure, neurologic symptoms, and deficient pituitary hormone secretion (gonadotropins are commonly affected); the latter results from compression of normal gonadotroph cells, which in turn leads to hypogonadism.

Transsphenoidal surgery (or, rarely, transfrontal surgery) performed by an experienced neurosurgeon is the only effective way to reduce tumor size (in 90% of patients), to relieve mass effects, and to suppress α-subunit hypersecretion [91], although usually not all adenoma tissue is removed (Figure 4). Vision improves in 70% of patients with preoperative visual-field defects [92]. Preexisting hypopituitarism often improves, but common early postoperative complications are diabetes insipidus and inappropriate secretion of antidiuretic hormone. Approximately 15% of tumors usually recur within 5 to 6 years after successful surgical resection. Adjuvant pituitary radiation therapy after transsphenoidal surgery may be offered to patients with residual adenoma tissue in an attempt to prevent future tumor regrowth. Observation may be recommended for asymptomatic adenomas that do not immediately threaten vision.

Nonfunctioning pituitary tumors respond poorly to dopamine agonist treatment, with modest tumor shrinkage in less than 10% of patients [13]. Bromocriptine has been reported to suppress supranormal levels of follicle-stimulating hormone [93, 94], luteinizing hormone [95], and α-subunit concentrations [94, 95] in a few patients; most patients do not benefit from dopamine agonist therapy.

Somatostatin receptor subtypes 2 and 5 have been identified on nonfunctioning human pituitary adenomas [41, 42]. Octreotide, however, only mildly suppressed serum gonadotropin and α-subunit levels [96, 97]. Vision improved [96, 97] and tumor size decreased [97, 98] in several patients with macroadenomas treated with octreotide. Of note, vision may improve without documented tumor shrinkage [96, 97]. Thus, most patients with nonfunctioning tumors do not respond clinically or biochemically to octreotide treatment.

Long-term administration of gonadotropin-releasing hormone agonists to normal persons down-regulates gonadotropin-releasing hormone receptors on normal gonadotroph cells and decreases gonadotropin secretion. In patients with gonadotroph adenomas, however, these agonists produce either agonist effects or no effect on hormone secretion, with no effect on adenoma size [99]. The selective gonadotropin-releasing hormone antagonist Nal-Glu GnRH, given to patients with gonadotroph adenomas and elevated serum follicle-stimulating levels, suppressed hormone hypersecretion but had no effect on adenoma size [100]. Thus, tumor mass, the important clinical feature of these tumors, appears independent of the hypothalamic drive.

In summary, novel pharmacologic treatments attempted for these tumors have not proven successful, and transsphenoidal surgery is still the only method available for large, symptomatic, nonfunctional pituitary adenomas. However, asymptomatic small adenomas with no threat to vision may be followed with no need for immediate intervention.

Integrated Approach to Therapy

The management of pituitary tumor is multimodal. Surgery, radiation, and medical treatment are available therapeutic options, each with relative advantages and disadvantages. The primary approach depends on the type of tumor diagnosed. Generally, patients with nonfunctioning tumors benefit from surgical excision, as will most patients with Cushing disease, TSH-producing adenomas, and small growth hormone-secreting adenomas. Patients with prolactinomas and those who have growth hormone-cell or TSH-cell adenomas after surgical excision with persistent growth hormone or TSH hypersecretion will benefit from medical therapy, as will patients with persistent ACTH secretion after surgery. Postoperative radiation therapy may be indicated for nonfunctioning tumors, as well as for secreting tumors resistant to medical therapy. The decision about which therapy to use also depends on the patient's general health, ability to withstand anesthesia, tolerance of expected side effects (for example, postirradiation hypopituitarism), and cost. Thus, the management decision should reflect these multifactorial considerations, which ultimately provide the patient with an evidence-based decision about therapy.

An internist may initiate pharmacologic therapy for prolactinomas, whereas an endocrinologist is usually required to initiate treatment for acromegaly, Cushing disease, and nonfunctioning tumors. Nevertheless, the internist should coordinate clinical care for associated conditions, including pituitary hormone replacement, diabetes, cardiac failure, osteoporosis, and arthritis. Because most of the specific therapies described in this review require long-term or even lifelong monitoring, familiarity with adverse reactions and side effects is important for follow-up.

Dr. Melmed: Cedars-Sinai Research Institute, University of California, Los Angeles, School of Medicine, Room 2015, 8700 Beverly Boulevard, Los Angeles, CA 90048.