Pharmacologic Aspects

There are currently three dopamine agonists available in the treatment of prolactinomas: cabergoline, bromocriptine, and quinagolide (Table 17-1).

The semisynthetic ergot derivative, bromocriptine, a D2 agonist and weak D1 antagonist, was the first available medical treatment for prolactinomas. Administered orally, bromocriptine has a relatively short half-life (7 hours), often necessitating two to three daily doses, although once daily dosing may occasionally be effective. The standard dosage is 2.5 to 15 mg per day, and most patients are successfully treated with 7.5 mg or less.⁶ Since gastrointestinal side effects are common, it is usually recommended to start with very low doses (1.25 mg/day) and gradually titrate upward by 1.25 mg increments weekly until a dose of 7.5 mg is reached.⁶ In resistant patients, doses as high as 20 to 30 mg per day may be necessary.

Cabergoline, a preferential D2-receptor agonist, has largely supplanted bromocriptine as the first-line treatment of prolactinomas due to its superior efficacy, longer half-life, and greater tolerability. Its half-life of 2.5 to 4.5 days allows for once or twice weekly administration.⁷ The typical starting dose of cabergoline is 0.25 mg orally once or twice weekly, with escalation of dosing by 0.25-mg increments at 2- to 3-month intervals if plateau effect is reached, until prolactin levels normalize. In most patients, the therapeutic dose range is 0.5 to 3.5 mg weekly. A recent study found that more than 95% of patients are able to achieve normal prolactin levels with high-dose treatment (from 6 to 11 mg/wk).⁸

Quinagolide is a non-ergot derivative D₂-receptor agonist commonly used to treat prolactinomas in Europe and Canada. The half-life of quinagolide is 22 hours, which allows for a once-daily dosing regimen. As with cabergoline, the simpler dosing regimen and reduced side effect profile of quinagolide allows for better patient compliance compared with bromocriptine. Typical doses are 0.075 mg to 0.4 mg daily, and most patients are effectively treated with 0.1 mg/day. This drug can be rapidly titrated to therapeutic doses in just 7 days: a starting dose of 0.025 mg is given for 3 days and is titrated by 0.025 mg every 3 days until a dose of 0.075 mg is achieved.

Therapeutic Efficacy

For microprolactinomas, bromocriptine is 80% to 90% effective at normalizing prolactin levels and shrinking tumor mass, whereas the success rate is around 70% for macroprolactinomas.² The improvement in headache and visual field defects is rapid and dramatic in most patients, occurring within a few days after the first dose. These changes often precede radiographic evidence of tumor shrinkage. Likewise, gonadal and sexual function may improve even before complete normalization of serum prolactin levels, although sometimes normalization of testosterone may require several months of normal prolactin levels². The degree of tumor shrinkage seen with bromocriptine does not necessarily correlate with the nadir prolactin level or the extent of decline in prolactin levels.² Although most prolactinomas remain responsive to bromocriptine over time, the drug is generally not curative, as hyperprolactinemia and tumor growth will often recur after withdrawal of therapy. Prolonged use of bromocriptine has been associated with perivascular fibrosis and increased tumor consistency in prolactinomas that ultimately are surgically removed; the extent of fibrosis seems to correlate with the duration of pre-surgical treatment with bromocriptine and may impact the technical ease of surgical resection.⁹

Early studies found cabergoline to be 80% to 95% effective at normalizing prolactin levels, with varying degrees of tumor reduction seen in 70% to 90% of patients.¹⁰ The efficacy of cabergoline in normalizing prolactin levels in micro- and macro-prolactinomas is shown in Tables 17-2 and 17-3, respectively. Although there is considerable variability among studies with respect to tumor shrinkage, a recent large study showed a significant (>50%) tumor shrinkage in 80% of patients, and complete disappearance of the tumor mass in 57% of patients.¹¹ Cabergoline is able to induce tumor shrinkage more effectively in dopamine agonist naïve patients compared with those who have received prior dopamine agonist treatment (Fig. 17-1). Furthermore, cabergoline offers the potential for cure after several years of treatment, allowing for withdrawal of therapy.^{12, 13}

FIGURE 17-1 Efficacy of cabergoline on tumor shrinkage in patients with macroprolactinomas. BRC, bromocriptine.

(From Vilar L, Freitas MC, Naves LA, et al. Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients. J Endocrinol Invest. 2008;31:436-444. Editrice Kurtis.)

The beneficial effects of cabergoline on gonadal function are well documented in both sexes. Compared with bromocriptine, cabergoline is more effective at normalizing prolactin levels and restoring ovulation and is associated with fewer, milder, and shorter-lived side effects.¹⁴ Serum testosterone levels have been shown to normalize in the majority of patients, with concurrent improvement in sperm count and parameters.¹⁵

Quinagolide normalized prolactin levels in 73% of patients with microadenomas and 67% of patients with macroadenomas.¹⁶ Tumor reduction was seen in 55% of patients with microadenomas and 75% of patients with macroadenomas.¹⁶ Although cabergoline has been found to be more effective at normalizing prolactin levels and reducing tumor size compared with quinagolide, both drugs show similar efficacy on reproductive function.

Pergolide, a semisynthetic ergoline derivative, was initially approved in the United States only for the treatment of Parkinson’s disease. Typical doses used in the treatment of hyperprolactinemia range from 0.05 mg to 0.5 mg/day, whereas higher doses (>3 mg/day) have been used in Parkinson’s patients.¹⁷ Although pergolide has been found to be effective at normalizing prolactin levels and reducing the size of macroprolactinomas, this drug was withdrawn from the U.S. market in 2007 due to the increased risk of valvular heart disease in Parkinson’s patients receiving high daily doses.

Tolerability and Side Effects

The most common side effects of dopamine agonists include gastrointestinal, cardiovascular, and neurologic symptoms (Table 17-4). In general, if a patient cannot tolerate the first dopamine agonist administered, a trial of a second drug should be given.

Table 17-4 Side Effects of Dopamine Agonists

Among the dopamine agonists, bromocriptine is the least well tolerated, with up to 12% of patients being unable to tolerate therapeutic doses.² Up to one third of patients will experience nausea and vomiting, an effect that can be minimized by initiating a low dose and titrating very slowly.² Taking the medication with a small snack may also reduce these symptoms.² A gradual dose titration and taking the medication at bedtime may also help reduce postural hypotension and dizziness experienced by as many as 25% of patients.² Syncope is rare but has been reported even with small initial doses.¹⁸ Tolerance to postural hypotension usually develops rapidly.¹⁸ Drowsiness, headache, and nasal congestion are common complaints. The safety of bromocriptine in psychiatric patients has not yet been established; there are case reports of onset or exacerbation of preexisting psychosis. Other psychiatric symptoms associated with high doses of bromocriptine include anxiety, depression, insomnia, paranoia, and hyperactivity.¹⁸ At higher doses used in the treatment of Parkinson’s disease, reversible pleuro-pulmonary changes and retroperitoneal fibrosis have been reported, but these changes are unlikely to occur at the doses used to treat prolactinomas.²

While cabergoline and bromocriptine have similar side effect profiles, cabergoline has been shown to be better tolerated in several large comparative studies.^{11, 19} Compared with bromocriptine, the side effects of cabergoline are generally less frequent, milder, and of shorter duration.² Nausea and vomiting are most commonly observed, followed by headache and dizziness.² In a multi-center randomized trial of hyperprolactinemic women, 3% could not tolerate cabergoline compared with 12% who had to stop taking bromocriptine.¹⁴ It has been proposed that fluctuations in concentrations of dopamine agonists are the main cause of side effects; cabergoline would be better tolerated due to its long half-life and relatively steady plasma concentration.¹⁸

Quinagolide has also shown better tolerability compared with bromocriptine. In a double-blind comparative study of 47 hyperprolactinemic patients, quinagolide was tolerated by 90% of patients versus 75% of patients treated with bromocriptine.²⁰ As with the other dopamine agonists, the most frequent side effects include nausea, vomiting, headache, and dizziness. These effects are transient and occur within the first few days of starting therapy or during dose adjustments.¹⁸

Dopamine Agonists and Valvular Heart Disease

Recently, the safety of dopamine agonists has been brought into question after two large population-based studies showed an increased risk of cardiac valvular disease in Parkinson’s disease patients being treated with high doses of these drugs, and particularly cabergoline and pergolide.^{21, 22} It is now recognized that one of the “off target” effects of dopamine agonists is activation of the serotonin (5-HT) receptor, of which there are 7 distinct subtypes.²³ High concentrations of the subtype 5-HT2B receptor are found on cardiac valves and the pulmonary arteries.²³ Both pergolide and cabergoline have been implicated in the development of cardiac valvular fibrosis because of their agonist effects at the 5-HT2B receptor.²³ Bromocriptine, which is only a partial agonist at the 5-HT2BR, had until recently not been thought to pose an increased risk of cardiac valvular disease, as there had only been a single case report suggesting an association.²³ However, a recent prospective study suggests that bromocriptine may, in fact, be equally associated with the development of cardiac valvulopathy at high cumulative doses.²⁴

Several studies have recently examined the effect of cabergoline on cardiac valvular disease in patients with prolactinomas.²⁵ These patients typically receive much lower doses (10–20 times less) than in Parkinson’s disease. Only one of seven studies available to date showed an association between cabergoline use and valvular regurgitation. In this study, there was an increased risk of moderate tricuspid regurgitation in patients who had received cumulative cabergoline doses greater than 280 mg.²⁶ However, in another study, patients receiving cabergoline (0.25–4 mg/wk) for 3 to 4 years (mean cumulative dose of 311 mg), had no increased prevalence of clinically significant valvular heart disease.¹⁶ Even in patients treated with cabergoline for 8 years who received cumulative doses as high as 1728 mg, there was no increased risk of clinically relevant heart disease.²⁸

Therefore, conventional doses of cabergoline used to treat prolactinoma patients do not currently appear to pose an increased risk of cardiac valvular disease. However, until larger prospective studies clarify the issue, it may be prudent to monitor patients requiring higher doses of cabergoline (>2 or 3 mg/wk) with serial echocardiograms. If valvulopathy develops, it may be reasonable to switch to bromocriptine. Alternatively, surgical resection may be appropriate. This issue underscores the importance of using the smallest effective dose and attempting withdrawal from cabergoline treatment in patients who achieve normalization of prolactin levels and significant tumor shrinkage to minimize their cumulative lifetime exposure to the drug.²⁵

Dopamine Agonists and Pregnancy

Two principal considerations arise in the management of women with prolactinomas who either desire fertility or who become pregnant: (1) the risk of tumor growth due to physiologic stimulation of tumoral lactotrophs induced by pregnancy, and (2) the effects of dopamine agonists on fetal development. These two considerations should be weighed against each other on an individualized basis, taking into account the size of the patient’s initial tumor, response to treatment, and the patient’s ability to tolerate side effects of treatment. It has been estimated that the risk for significant tumor enlargement during pregnancy is 1.6% to 5.5% in microprolactinomas and 15.6% to 35.7% in macroprolactinomas.¹⁸

Generally, discontinuation of dopaminergic therapy is recommended at the time of diagnosis of pregnancy in patients with microadenomas because the risk of tumor growth overall is quite low. Visual field exams should be performed each trimester and the patient should be told to report any new headache pattern or visual disturbances; dopamine agonists should be resumed and titrated up rapidly if there is MRI evidence of significant tumor growth.

For patients with macroadenomas, especially those in close proximity to the optic chiasm or cavernous sinuses, contraception should be encouraged while attempting to reduce the size of the tumor prior to pregnancy. If a patient with a macroprolactinoma becomes pregnant, there are several different therapeutic approaches that can be offered: (1) dopamine agonists may be stopped after conception with neuro-ophthalmological exams performed throughout pregnancy, (2) dopamine agonists may be continued throughout pregnancy, (3) trans-sphenoidal surgery may be performed in later stages of pregnancy if the enlarged tumor does not respond to resumption of dopamine agonists, or (4) delivery if tumor growth cannot be controlled and the pregnancy is advanced enough.²

Bromocriptine has conventionally been the drug of choice in women with prolactinomas who desire fertility or who become pregnant. There is substantial evidence showing that exposure to bromocriptine at the time of conception does not cause birth defects or increase the risk of spontaneous abortions, ectopic pregnancies, trophoblastic disease, or multiple pregnancies.²⁹ However, evidence is also accumulating to show that cabergoline may have an equally good safety record in terms of pregnancy outcomes.³⁰ A recent 12-year prospective study of cabergoline use in 329 pregnancies showed no increased risk of miscarriage or fetal malformation.³⁰

Dopamine Agonist Resistance

A subset of patients with prolactin-secreting pituitary tumors demonstrate “biochemical” resistance (failure to normalize prolactin levels) or “mass” resistance (absence of tumor shrinkage) to dopamine agonists.² Resistance to dopamine agonists occurs in both micro and macro-adenomas and is believed to be mediated by the downregulation of pituitary D2 receptors.³¹ Biochemical resistance has been estimated to occur in approximately 10% to 20% of patients on dopamine agonists. Mass resistance has been estimated to occur in approximately 30% to 40% and 15% of patients to bromocriptine and cabergoline, respectively.^{2, 31} The prevalence of resistance to quinagolide is unclear given the lack of data regarding its use in dopamine-agonist naïve patients.⁶

Most tumors resistant to bromocriptine will respond to cabergoline. When switched to cabergoline, 85% of patients resistant to bromocriptine and quinagolide achieved normal prolactin levels, and 70% had some change in tumor size.³² A recent large study showed that cabergoline normalized prolactin levels in 61% and 50% of bromocriptine-resistant microprolactinomas and macroprolactinomas, respectively.¹¹

Therapeutic options in the management of dopamine-resistant prolactinomas include (1) increasing the dose of the dopamine agonist, (2) switching to an alternative dopamine agonist, (3) trans-sphenoidal surgery, and (4) radiation therapy. In most cases, the resistance to dopamine agonist is partial, and a response can be achieved by progressively increasing the dose of the drug. A recent study showed that in more than 95% of patients resistant to bromocriptine prolactin normalized with individualized high-dose cabergoline treatment (mean dose 5.2 mg/wk).⁸ Bromocriptine-resistant patients generally require higher doses of cabergoline and have less tumor shrinkage compared to treatment-naïve patients.³³ In general, switching from cabergoline to bromocriptine is unlikely to be efficacious.

While trans-sphenoidal surgery is never a first-line treatment for macroprolactinomas, it remains an important option for patients who cannot tolerate dopamine agonists or when medical therapy is ineffective at controlling symptoms or restoring reproductive function. There is little long-term outcome data regarding patients with macroprolactinomas treated with dopamine agonists who subsequently proceed to surgery. In a recent study of 72 patients, 35% of patients required trans-sphenoidal surgery due to resistance and/or intolerance of dopamine agonists.³⁴ This study, which an outlier given the disproportionately high number of dopamine agonist resistant patients, showed that additional tumor shrinkage was achieved in 57% of operated patients, while only 22% were able to attain normoprolactinemia without dopamine agonists following surgery.³⁴ Surgery was associated with a high incidence of hypopituitarism regardless of whether patients received subsequent radiotherapy.³⁵ The remission rate for surgery when used as second-line treatment for prolactinomas is quite low (around 22%). As opposed to its curative role in the other secretory macroadenomas, surgery plays only a “debulking” role in macroprolactinomas, and therefore should be reserved for patients who, despite maximal medical therapy, have progressive tumor enlargement and are at risk of visual compromise or neurological deficits.³⁵

Conventional fractionated radiation therapy should be considered a last-line option in the management of dopamine-resistant prolactinomas given the delayed treatment effects and the high rate of panhypopituitarism. On the other hand, radiosurgery may be an effective treatment in secretory pituitary adenomas, with a lower risk of long-term hypopituitarism.³⁶

Dopamine Agonist Withdrawal

The optimal duration of therapy for patients with prolactinomas is uncertain. Until recently, dopamine agonist treatment had been considered a “lifelong” requirement. However, after a landmark study by Colao et al. demonstrated disease remission in a considerable proportion of patients following withdrawal from cabergoline, attention shifted towards defining selection criteria for withdrawal and identifying predictors of long-term remission.^{12, 37} Defining the optimal timing and appropriate candidates for withdrawal is difficult because of the heterogeneity of studies that have examined this issue, which differ with respect to the causes of hyperprolactinemia (idiopathic vs. micro/macroprolactinoma), the type and duration of dopamine agonist treatment, and the treatment prior to the start of dopamine agonist therapy.³⁸ Despite the inherent difficulty in extrapolating from these disparate studies, the Pituitary Society has proposed certain criteria for withdrawal, including (1) normoprolactinemia and (2) tumor absence or markedly reduced tumor volume after a minimum of 1 to 3 years of dopamine agonist treatment.³⁹ A recent study tested the applicability of these criteria and found a recurrence rate of 54% after withdrawal of long-term cabergoline treatment.¹³ In this study, most patients had recurrence of disease within 1 year of discontinuation, and a similar recurrence rate (52% vs. 55%) was seen in patients with microprolactinomas and macroprolactinomas.¹³ The size of the tumor remnant prior to withdrawal appears to be predictive of recurrence risk.¹³

A recent meta-analysis showed that long-term remission occurs in only 21% of patients following dopamine agonist withdrawal.³⁸ The best chance for a long-term remission is seen in patients treated with cabergoline for more than 2 years, with a mean remission rate around 54%, whereas remission is seen in only 20% of patients withdrawn from bromocriptine.³⁸ Considering the financial burden, occasional problems with tolerability, and potential risk of valvulopathy with long-term dopamine agonist treatment, it is reasonable to attempt withdrawal in patients who have been on a dopamine agonist (particularly if cabergoline) for 2 years or more.