Medical Treatment of Pituitary Adenomas

Surgical treatment of pituitary tumors has been available since the turn of the previous century, and radiation therapy for nearly as long, but the medical treatment of these neoplasms is relatively new. Nevertheless, rapid advances have been made in the drug therapy of pituitary tumors.

Dopamine inhibits the secretion of prolactin by the pituitary lactotropes. In the baseline state of the normal pituitary gland, the secretion of prolactin (PRL) is tonically inhibited by dopamine carried from the hypothalamus to the pituitary through the hypophyseal portal circulation; blood PRL concentration is increased by interruption of this circulation as well as by PRL-secreting pituitary tumors. The use of dopamine agonists in the treatment of PRL oversecretion is based on the suppressive action of dopamine in normal and neoplastic pituitary glands. Dopamine agonists exert their effect by substituting for a deficiency of dopamine or by saturating dopamine receptors whose number (or affinity) is changed, as is the case with prolactinomas.

In addition to their effects on PRL secretion, dopamine agonists are often effective in decreasing the secretion of growth hormone (GH) in acromegaly, but the mechanism by which they work is not clear. Paradoxically, dopamine increases the secretion of GH from normal pituitaries, but in many (though not all) acromegalics it suppresses GH output. The therapeutic use of dopamine agonists capitalizes on this paradoxical response.

In addition to inhibiting hormone secretion, dopamine agonists reduce the size of PRL-secreting (and possibly, GH-secreting) tumors in most patients. The mechanism by which dopamine agonists reduce tumor size appears to be complex: a rapid initial phase of cell shrinkage is followed by long-term cytostatic and possibly cytocidal effects, producing fibrosis and some necrosis. Dopamine agonists diminish the number and size of intracellular organelles responsible for PRL secretion, but this effect reverses rapidly after drug withdrawal, suggesting the need for long-term (although not necessarily permanent) treatment of prolactinomas.

The dopamine agonists that are useful in the treatment of prolactinomas and are available are the ergot derivatives bromocriptine mesylate (Parlodel) and pergolide mesylate (Permax). A number of other ergoline drugs (lisuride, cabergolide, mesulergin) and nonergoline drugs (CV 205-502) are available. Dopamine agonists differ from one another in potency, duration of action, and, to some extent, side effects. All seem to exert their therapeutic effect by binding to D2 dopamine receptors. We will focus on bromocriptine because it has been the most widely used and remains the standard of therapy.

Bromocriptine, given by mouth, provides effective blood levels for 8 to 12 h. Consequently the drug is usually given two to three times per day. Daily doses ranging from 2.5 to 7.5 mg have been effective for the treatment of microprolactinomas, and doses from 5.0 to 12.5 mg for macroprolactinomas. Bromocriptine therapy can arrest the growth of prolactinomas, but it is not certain that it can cure them. Thus, the medication must be administered for an indefinite length of time, possibly for the lifetime of the patient. Withdrawal of chronic dopamine agonist therapy must be accompanied by careful and continued surveillance of blood PRL levels and radiographic monitoring for tumor regrowth.

Side effects from bromocriptine, especially gastrointestinal disturbances and orthostatic hypotension, are relatively common but usually transient and mild. Nausea and vomiting occur acutely in 25 percent of patients and chronically in 6 to 10 percent of patients. Orthostatic hypotension can occur initially in 25 percent of patients and persists in 6 to 10 percent. The incidence and morbidity of these side effects can be minimized by administering the initial doses at bedtime, by slowly increasing the dose to effective levels, by having the patient take the medication with meals, and by using the smallest dose needed to suppress PRL. One patient with severe gastrointestinal side effects from oral bromocriptine was able to achieve excellent blood levels and a good clinical response when the drug was given intravaginally. There have been rare reports of psychotic reactions to dopamine agonists, most commonly in patients with a history of previous psychiatric illness who were treated concurrently with both bromocriptine and antipsychotics.

There is at present no evidence of multiple pregnancies or teratogenesis attributable to the drug, but most authorities recommend stopping bromocriptine as soon as a woman becomes pregnant and resuming immediately after delivery, especially if there is evidence of tumor enlargement. Fortunately, a study of 64 children born to 53 women treated during all or part of pregnancy with bromocriptine revealed no increased incidence of physical or mental developmental problems. Children and adolescents suffering from prolactinomas have been safely and effectively treated with bromocriptine

Long-acting intramuscular and oral forms of bromocriptine have proved clinically effective. Therapeutic levels are reached within 2 h after injection, and initial reports indicate a much lower incidence of side effects. The intramuscular form is usually administered in a single injection, after which the patient is started on oral bromocriptine.

Pergolide, another oral dopamine agonist, is 100 times more potent and is longer acting than bromocriptine. Its side effects are similar to but less frequent than those encountered with bromocriptine. The lower incidence of side effects sometimes allows the successful use of other dopamine agonists to treat patients who are resistant to or unable to tolerate bromocriptine.

Long-lived analogues of somatostatin permit the treatment of some pituitary tumors. Octreotide acetate is a synthetic octapeptide that suppresses the secretion of GH and TSH for clinically significant periods. Octreotide has reduced hormone levels, and sometimes tumor size, in patients with acromegaly or thyrotropinomas. Octreotide is commercially available for treatment of tumors refractory to conventional surgery or radiation therapy. Drawbacks to its use include the necessity for subcutaneous injection two or three times a day and its great expense (many hundreds of dollars each month). Side effects include diarrhoea, steatorrhea, glucose intolerance, and an increased frequency of gallstones, but in general the drug seems to be reasonably well tolerated.

The drug responsiveness of specific pituitary adenomas varies depending on the hormone (if any) secreted by the tumor. Likewise, the drugs to be used vary on the same basis

Evans and Thorner commented on the difficulty of choosing surgery or drug therapy as the single best form of treatment for prolactinoma. In part, this difficulty arises because the outcome of surgical treatment varies with the size of the tumor at initial treatment (better outcomes with smaller tumors), and in part it reflects the fact that some patients and physicians prefer a treatment that may provide a cure (surgery) rather than one that controls the lesion by indefinite daily drug taking.

Prolactin-secreting tumors are arbitrarily classified as microprolactinomas (10 mm in diameter or less) or macroprolactinomas (greater than 10 mm in diameter). Elevated PRL levels discovered serendipitously in truly asymptomatic individuals (those without amenorrhea, galactorrhea, impotency, headache, infertility, osteopenia. or visual disturbance) require no treatment regardless of whether there is radiographic evidence of a microprolactinoma, because it is uncertain that the risks of treatment are less than those of the hyperprolactinemia. However, both these patients and those who have definite symptoms and undergo treatment need regular and long-term hormonal and radiographic monitoring.

Patients with a microadenoma stand a very good chance of achieving normal post-treatment prolactin levels with either surgical or medical treatment. Up to 80 percent of such patients achieve normal serum PRL levels after transsphenoidal adenomectomy, but there is a substantial recurrence rate of hyperprolactinemia (possibly up to 50 percent of cases) after even apparently successful surgery. The results of dopamine agonist therapy in normalizing serum PRL are comparable to those of surgery. Prolactin levels fall into the normal range and symptoms disappear in up to 95 percent of patients treated with bromocriptine

Since there is a high likelihood of postoperative recurrence and since dopamine agonists are generally well tolerated, it is logical to consider the initial therapy of microprolactinomas should take the form of a trial of dopamine agonist therapy, however. surgery is an appropriate choice in the early treatment of those patients who manifest intolerance to dopamine agonists or resistance to their action. Occasionally, a patient's wish to become pregnant has been cited as an indication for surgery, but there is no firm evidence that dopamine agonists are contraindicated before or during pregnancy or that pregnancy itself is a substantial risk in patients with a microprolactinoma.

The treatment of macroprolactinomas is more problematic than that of microprolactinomas. Symptoms are frequently more severe. and visual loss or other neurological deficits are ever-present possibilities; tumor growth must be arrested if at all possible. Radiation therapy reduces tumor size and decreases prolactin secretion. but the response is so slow that this treatment modality is generally not the first choice. On the other hand, the use of dopamine agonists to control tumor growth and hyperprolactinemia may permit the use of radiation therapy even in patients with macroprolactinomas.

Surgery has often been the treatment of first choice for macroprolactinomas, but the long-term results of surgical treatment are disappointing. The serum levels of PRL normalize in less than 50 percent of patients, and there is a very substantial recurrence rate (20 to 90 percent) even among those patients in whom prolactin levels do become normal. Patients with persistent or recurrent hyperprolactinemia need dopamine agonist therapy after surgery. Since most patients with macroprolactinomas will eventually receive dopamine agonists, and since the drugs are often effective against these tumors, an initial trial of medication is worthwhile. Impairment of visual acuity (not just minor constriction of visual fields) is one indication for prompt surgical resection, although a trial of dopamine agonists with careful ophthalmologic monitoring may be appropriate even in these cases.

The results of a prospective, multicenter study of primary bromocriptine treatment of macroprolactinomas are most encouraging. PRL levels normalized in 67 percent of patients and fell by 90 percent or greater in 26 of the 27 patients studied. Furthermore, the tumor shrank to some degree in all patients, and by 50% or more in 64 percent of the patients.

Bromocriptine should be considered as initial management for patients with PRL-secreting macroadenomas, even in the case of tumors that have extended outside the confines of the sella. Surgical intervention is indicated when visual or neurological loss progresses despite medical treatment, or when the tumor has produced cerebrospinal fluid leakage.

All patients, even those with microprolactinomas, for whom dopamine agonist therapy is chosen must be committed to longterm surveillance to be certain that tumor growth is arrested or reversed, that prolactin levels are normalized (if possible) and stabilized, that gonadal function is restored (to prevent the osteopenia of hypogonadism), and that visual function is preserved. Reduction of serum PRL is not by itself sufficient evidence of tumor response, since macroadenomas may sometimes grow despite a fall in serum PRL levels; radiographic surveillance is also needed. The dose of dopamine agonist must be adjusted upward, within the bounds of the patient's tolerance, until serum PRL is normalized.

High initial doses may be required to achieve control in the case of macroprolactinomas, but it may be possible to sustain improvement on a chronic basis with lower maintenance doses. The fact that some prolactinomas may fail to respond or may "escape" from dopamine agonist control indicates the need for careful, periodic monitoring of tumor activity in every case. Poor control may reflect problems in patient compliance, an insufficient dosage or potency of the drug (the latter indicating a need to change to a more potent drug if available), or a nonresponsive tumor type (for example, a non-prolactin-secreting tumor which was mistaken for a prolactinoma because it compressed the pituitary stalk, interrupting the normal flow of dopamine from hypothalamus and thereby causing hyperprolactinemia-a so-called "pseudoprolactinoma"). In most instances, dopamine agonists will provide lasting benefit, but on those occasions when surgical removal of the tumor becomes necessary, the success of the resection does not appear to be impaired and may even be improved by prior treatment with bromocriptine

Acromegaly

As in the case of prolactinomas, drug treatment offers hope for clinical improvement in, if not complete control of, disordered growth hormone secretion. Surgery and radiation therapy (or both) have been the standard forms of treatment, but both have drawbacks. Surgery is not always permanently effective, especially in patients with large tumors. Radiation therapy can be effective in decreasing GH levels and reducing tumor size, but these benefits take up to 10 years to become apparent.

Dopamine Agonist Treatment

Because of the lack of a totally satisfactory response to either surgery or radiation therapy and because of the occasional unwanted effects of radiation (including complete or partial hypopituitarism and radiation damage to extrapituitary neural tissue), efforts have been made to find a successful drug therapy for acromegaly. Dopamine agonists were the first drugs proved to be effective (10 to 80 percent of patients respond) in reducing GH levels, ameliorating reversible symptoms of acromegaly, and shrinking tumor size, especially in those instances where there is a coincident hypersecretion of PRL. Oppizzi et al. showed that patients with acromegaly in whom the plasma GH level fell by 50 percent after a single oral dose of bromocriptine or lisuride had a favourable long-term response to dopamine agonists.

In addition to their use as primary treatment in acromegaly, dopamine agonists can be used effectively as adjunctive agents in cases where surgery has not proven completely curative, or following radiation therapy to lower GH levels while waiting for the effects of radiation to develop. Preoperative use of dopamine agonists is not warranted in acromegaly because the agents shrink the tumor in only a minority of cases, and there is no evidence that their use improves the results of surgery. The dose of bromocriptine needed for successful treatment of acromegaly, even in responsive patients, is generally higher (in the range of 10 to 60 mg per day) than the effective dose for prolactinomas; other dopamine agonists seem to be effective when used in appropriate doses.

Somatostatin Analogue Treatment

Somatostatin was originally detected because extracts of mammalian hypothalamus were able to suppress the secretion of GH by pituitary cells in culture, Somatostatin is cleared from the circulation too rapidly to be therapeutically useful, but a long-acting analogue, octreotide, has proved successful in the treatment of acromegaly. In their review, Lamberts and colleagues point out that a substantial majority of acromegalic patients treated with octreotide achieve normal GH levels (and in a further large group, GH levels are markedly reduced).

Octreotide is usually given by subcutaneous injection (50 µg every 8 h), but a dose size of 100 µg or more may be necessary. The success of experimental intranasal application or continuous subcutaneous infusion of octreotide suggests that novel methods of administration may be forthcoming. Octreotide takes effect rapidly, giving prompt relief of headache, sweating, and weakness and prompt reduction of GH levels; there is also a decrease in the size of the pituitary tumor in some patients.

Gastrointestinal side effects (nausea, steatorrhea) are common early in treatment, but rarely necessitate stopping treatment. An increased formation of gallstones is a worrisome effect of long-term treatment. Octreotide seems to be effective in the treatment of acromegaly and is commercially available but, because of its great expense, its use is best reserved for individuals in whom surgery is not possible or has been unsuccessful or in whom the slowly developing effects of radiation therapy have not yet occurred

ACTH-Secreting Pituitary Tumors

Transsphenoidal hypophyseal surgery is clearly the treatment of choice in Cushing's disease, and a combination of surgery and radiation therapy in Nelson's syndrome. Attempts at pharmacologic suppression of ACTH with bromocriptine, cyproheptadine, sodium valproate, and octreotide have proved generally unsatisfactory, but there are occasional reports of success with these agents. In desperate circumstances they may be worth a try, although it is usually better in such cases to use drugs that directly inhibit cortisol synthesis by the adrenal cortex, such as aminoglutethamide (Cytadren), metyrapone, mitotane and ketoconazole.

Thyrotropin-Secreting Pituitary Tumors

TSH-secreting adenomas produce hyperthyroidism and are thus distinguished from the pituitary enlargement secondary to TSH hypersecretion that is sometimes seen in patients with primary hypothyroidism. Neither surgery nor a combination of surgery and radiation therapy is satisfactory as the primary treatment for TSHsecreting pituitary adenomas, because of the aggressive growth and poor radiation response of these tumors. Bromocriptine can suppress TSH hypersecretion in some cases, but long-term therapy has generally been unsuccessful. More promising is the use of octreotide. Comi and colleagues obtained satisfactory responses in four of five patients treated with octreotide, in one of whom control remained good throughout an 18-month period. Their results bode well for patients with unresectable, uncontrollable, or residual thyrotropin-secreting adenomas.

Gonadotropin-Secreting Pituitary Tumors

Pituitary adenomas that secrete gonadotropin (GnH) are fortunately rare and are best treated with surgery or radiation. Bromocriptine has been used with apparent benefit in isolated cases, and the experimental dopamine agonist CV 205-502 has been reported to be helpful. Analogues of gonadotropin releasing hormone (GnRH) did not help two patients with gonadotropin-secreting pituitary adenomas.

Nonfunctioning Pituitary Tumors

Since nonfunctioning pituitary tumors produce no hormonal symptoms, they are often quite large when detected (usually as a result of visual symptoms). Primary treatment consists of surgical resection. Bromocriptine has been given to such patients and has occasionally resulted in improvement in visual fields and arrest of tumor growth, but the tumors rarely shrink. There is no clear role at present for medical treatment of nonsecretory pituitary adenomas.