Long-Term Treatment of Prolactin-Secreting Macroadenomas with Pergolide

Pamela U. Freda, Charalambos I. Andreadis, Alexander G. Khandji, Maha Khoury, Jeffrey N. Bruce, Thomas P. Jacobs and Sharon L. Wardlaw

Departments of Medicine (P.U.F., C.I.A., M.K., T.P.J., S.L.W.), Neurosurgery (J.N.B.), and Radiology (A.G.K.), Columbia University College of Physicians and Surgeons, New York, New York 10032

Address correspondence and requests for reprints to: Dr. Pamela U. Freda, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.


    Introduction
 Top
 Introduction
 Case Report (Case 1)
 Report of Series
 Discussion
 References
 
Although most PRL-secreting pituitary tumors are microadenomas at presentation, many, and particularly those in men, are macroadenomas at the time of diagnosis. Microprolactinomas typically present because of PRL-induced menstrual disturbance or galactorrhea in women and symptoms of hypogonadism in men. Macroprolactinomas (i.e. tumors >10 mm), however, often present because of symptoms of mass effect by the tumor, such as visual field loss, headache, other neurological symptoms or hypopituitarism. Therefore, the initial treatment of macroprolactinomas includes tumor shrinkage with relief of neurological symptoms, in addition to the lowering of PRL and restoration of gonadal function.

Medical therapy with dopamine agonists is now the preferred primary treatment of patients with prolactinomas. The dopamine agonist bromocriptine (BC) has been available and extensively used in the United States since the early 1980s. BC normalizes PRL levels and gonadal function in the majority of patients and reduces tumor size in up to 70–80% of patients with prolactinomas (1, 2, 3). Disadvantages to its use include side effects such as nausea, postural hypotension, nasal stuffiness, and headache in up to 10% of patients, as well as the twice or thrice daily dosing administration required. Recently, the longer-acting dopamine agonist cabergoline has been introduced in the United States for therapy of macroprolactinomas. Cabergoline has been shown to normalize PRL levels in up to 73–83% of patients and to reduce tumor size in most patients (4, 5, 6). Cabergoline seems to be better tolerated than BC (6).

Another ergoline derivative, pergolide mesylate, effectively inhibits PRL secretion and is an option for the medical treatment of prolactinomas. This dopamine agonist is approximately 100 times more potent than BC and suppresses PRL secretion for up to 24 h after a single dose (7, 8), allowing effective control of hyperprolactinemia with once daily dosing. Pergolide is approved in the United States only for the therapy of Parkinson’s disease, where it has been used safely at doses more than 10 times those used for PRL-secreting tumors (9). It has advantages over BC in that it only requires once-a-day dosing and is approximately one fifth the cost. In short-term studies, pergolide has been shown to effectively lower PRL levels. Few studies, however, have examined the long-term outcome of pergolide therapy of macroprolactinomas. The number of macroprolactinomas, followed with imaging studies, is also very small, and no studies have reported tumor shrinkage with pergolide documented by magnetic resonance imaging (MRI). Before the availability of cabergoline, we treated many patients with pergolide as first-line therapy and have documented its efficacy in correcting endocrine abnormalities and in shrinking macro-prolactinomas. Even though cabergoline may now be first-line therapy in many patients, based on our experience, pergolide remains an important alternative for the treatment of prolactinomas in the United States. Therefore, we present one case in detail of a patient with a very large macroprolactinoma treated with pergolide alone and then report our experience with pergolide for the long-term treatment of 22 patients with macroprolactinomas.


    Case Report (Case 1)
 Top
 Introduction
 Case Report (Case 1)
 Report of Series
 Discussion
 References
 
A 42-yr-old physician presented for further evaluation and treatment of a macroprolactinoma. The patient had normal growth and development and went through normal puberty. He had been generally well, but since the birth of his second child 7 yr earlier, he noted a decrease in libido, which had worsened significantly and progressed recently to impotence. Laboratory testing was performed and revealed an elevated PRL level, and he was referred to our Neuroendocrine Unit.

The patient had experienced frontal and retro-orbital headaches for 10 yr, but he denied visual problems. He had a 15-lb weight gain over 6 yr, but denied fatigue and change in skin, shaving, or body hair.

On physical examination he was well appearing with a normal hair pattern. Visual acuity, cranial nerves, and visual fields testing were normal. There was no gynecomastia or galactorrhea, and testes were normal size. The remainder of his examination was normal.

Routine chemistries were normal. Endocrine studies showed a markedly elevated PRL level of 2800 ng/mL (nl < 20 ng/mL), LH level of 0.94 mIU/mL (nl < 10 mIU/mL), FSH level of 3.4 mIU/mL (nl < 10 mIU/mL), testosterone levels of 421 ng/mL and 330 ng/mL (nl 270-1070), T4 level of 7.11 (4.5–12.0), T3 uptake level of 0.93 (nl 0.66–1.27), TSH level of 2.17 (nl 0.38–4.7), free T4 index level of 7.65 (nl 6.33–12.4), and GH level of 0.7 ng/mL. A MRI was done and revealed a 3.5 x 2.5 x 4.2-cm sellar/suprasellar, cystic mass (Fig. 1Go, a and b).



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Figure 1. Coronal (a) and sagittal (b) gadolinium-enhanced T1-weighted spin-echo magnetic resonance images through the sella turcica before pergolide therapy in patient 1. The images show a 3.5 x 2.5 x 4.2-cm sellar/suprasellar and right parasellar mass. It compresses and distorts the optic chiasm, the floor of the 3rd ventricle, and extends into the right middle cranial fossa to compress the medial temporal lobe. The sagittal images additionally demonstrate compression and mass effect on the midbrain and upper pons.

 
The patient was begun on therapy with pergolide mesylate at a dose of 0.025 mg nightly that was increased over 1 week to 0.05 mg nightly. In 1 month, his PRL level fell to 200 ng/mL, by 2 months his PRL level was 37 ng/mL, and by 3 months of therapy his PRL level was 17 ng/mL. The patient tolerated the therapy well and noted marked improvement in sexual function and headaches within 1 month of therapy. His testosterone level fell initially at 1 month of therapy to 293 ng/mL and by 2 months to 171 ng/mL, but subsequently rose to 350 ng/mL by 5 months of therapy and has remained normal. His PRL level remains normal 20 months into therapy with 0.05 mg pergolide nightly. His sexual function and libido are completely normal. On MRI his tumor showed marked shrinkage by 3 months of therapy, and by 16 months of therapy the tumor had shrunk by 90% (Figure 2Go, a and b).



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Figure 2. Coronal (a) and sagittal (b) gadolinium-enhanced T1-weighted spin-echo magnetic resonance images after pergolide therapy in patient 1. The images show a 90% shrinkage in the size of the macroadenoma with a normal appearance to the suprasellar and right parasellar cistern with a normal optic chiasm and now a visualized, but minimally deviated, pituitary stalk toward the left side.

 

    Report of Series
 Top
 Introduction
 Case Report (Case 1)
 Report of Series
 Discussion
 References
 
We have examined the long-term outcome in 22 patients with macroprolactinomas who were treated in our Neuroendocrine Unit with pergolide. The series consists of 18 men (including case 1), ages 16–65 yr, and 4 postmenopausal women, ages 49–70 yr. These 22 subjects were taken from the 42 consecutive patients receiving treatment with pergolide in our Neuroendocrine Unit and were included only if they either received pergolide as primary therapy or if pergolide was initiated after a hiatus of at least 6 months from other medical therapy. Eighteen patients received pergolide as primary therapy. Two patients (5, 16) had undergone transsphenoidal surgery 6 and 8 yr before pergolide therapy. Three patients had previously been treated with BC (5, 8, and 22), which had been discontinued 20, 6, and 60 months before study entry, respectively. All values for PRL, other hormones, and pretreatment MRI reported as basal values are those obtained at the start of pergolide therapy.

The primary presenting complaint that led to the diagnosis in the 18 men included symptoms of hypogonadism in 4 (including galactorrhea or gynecomastia), pubertal delay in 1, and symptoms related to tumor mass effect in 9, including visual disturbance in 5, symptoms related to hydrocephalus in 1, new onset of seizures in 1, dizziness in 1, and neck pain in 1. Five men were diagnosed after the macroprolactinomas were incidentally noted on imaging studies of the region done for other reasons. Of the four women, one presented because of galactorrhea, two with visual symptoms, and in one the tumor was noted on a computed tomography scan done for unrelated neurological symptoms. No patient had any clinical features to suggest acromegaly or Cushing’s syndrome, and no patient was taking medication known to raise PRL levels.

Patients were begun on pergolide mesylate (Eli Lilly & Co., Indianapolis, IN) at a dose of 0.025 mg nightly, which was increased gradually as tolerated and to achieve as normal a PRL level as possible. PRL levels (in all patients) and testosterone levels (in men) were measured at baseline, frequently over the 1st year, then at least yearly thereafter. Frequent clinical assessments included monitoring of visual acuity and visual fields to confrontation.

Radiological assessment of the pituitary was performed at baseline, between 3 and 6 months after initiation of pergolide therapy and yearly thereafter. The MRI protocol consisted of coronal, sagittal, and axial scans of the head and sellar region performed before and after injection of gadolinium DPTA. All scans were read by one neuroradiologist (AGK), who was blinded to the clinical and biochemical responses of the patients. Maximal tumor diameter was measured in all three dimensions. An estimate of tumor volume was determined from these dimensions, and percentage decrease of tumor volume from baseline to each subsequent imaging interval was calculated.

Follow-up after pergolide therapy

PRL levels.The mean pretreatment serum PRL level was 2938 ± 780 ng/mL, with a range of 220–15,000 ng/mL. Patients were followed for a mean of 27.4 months (range, 9–64 months). Based on the most recent PRL level on pergolide therapy, the mean percentage decrease in PRL level was 97%; all patients had at least an 86% fall in PRL level. The mean nadir PRL level in the group overall was 59 ng/mL, with a range of 1–685 ng/mL. A normal PRL level of less than 25 ng/mL was achieved in 15 of 22 patients, and an additional 2 patients had near normalization of PRL level to 30 ng/mL (4 and 22). In those patients with normalization of PRL, this was achieved after a mean of 7.9 months of therapy with a range of 1–22 months. Table 1Go shows the pretreatment and nadir PRL levels in each patient.


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Table 1. Basal and postpergolide therapy PRL and testosterone levels in 22 patients with macroprolactinomas

 
The mean maintenance pergolide dose was 0.11 mg per day (range, 0.025 to 0.5 mg/day) (Table 1Go). Most patients were effectively treated with pergolide doses of 0.1 mg or less a day. Of the three patients who had previously been treated with BC, two patients (5 and 22) achieved similar control of the hyperprolactinemia with pergolide as with BC, and one patient (8) who did not normalize his PRL level with pergolide had not achieved normalization on BC.

Gonadal function.Of the 18 men studied, pretreatment testosterone levels were low in 17 (Table 1Go). Two of these men (4, 5) were treated with testosterone supplementation. One patient (18) had short stature and GH deficiency at diagnosis at the age of 16 and is being treated with GnRH analog therapy to suppress the onset of puberty during pergolide and GH therapy. Of the remaining 14 men with low baseline testosterone levels, testosterone levels rose spontaneously on average to 262% of baseline and normalized in 5 patients with pergolide therapy. Fourteen men had symptoms of hypogonadism such as decreased libido or potency before therapy, and these symptoms improved markedly or resolved in 10 of these patients spontaneously and in 2 others who were treated with testosterone supplements. Interestingly, the improvement in symptoms was not predictable based on changes in PRL or testosterone levels. For example, patient 1 presented with impotence despite a normal testosterone level and experienced marked improvement with a fall in PRL, but no rise in testosterone. By contrast, patient 10 has had normal sexual function despite persistent hyper-prolactinemia and mildly low testosterone levels. Of the four women studied (ages 49–70), one patient (21) had the brief resumption of menses after more than 10 yr of amenorrhea, which was followed by elevation of gonadotropin levels and primary ovarian failure.

Tumor size.All patients had macroadenomas before treatment. The mean maximal tumor diameter was 3.0 cm (range, 1.0–5.3 cm) before therapy (Table 2Go). Most tumors were very large with 77% (17 of 22) being 2.0 cm or greater and 55% (12 of 22) being 3.0 cm or greater in maximal diameter at presentation. All patients had significant tumor shrinkage over the treatment period. The mean tumor shrinkage was 66% (range, 23–99%). Tumor shrinkage was 23% or greater in all patients, 50% or greater in 19 patients, and 75% or greater in 9 patients.


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Table 2. Pituitary tumor size before and tumor shrinkage after pergolide therapy in 22 patients with macroprolactinomas

 
Neurological function.Six patients presented with visual field deficits ranging from superior temporal quadrant defects to bitemporal hemianopsia. Four patients had complete resolution of their deficits with pergolide treatment. One patient (5) had a longstanding fixed bitemporal deficit that did not resolve despite normalization of PRL and marked tumor shrinkage with adequate decompression of the optic chiasm. Patient 2 presented with hydrocephalus requiring emergent ventriculo-peritoneal shunt placement, as well as impairment of visual acuity and bitemporal visual field deficits. This patient had normalization of his PRL level and significant tumor shrinkage, which relieved the obstructive hydrocephalus. However, he had only partial recovery of a bitemporal visual field deficit and, because the tumor continued to impinge on the optic chiasm, he underwent transsphenoidal decompression of the tumor after 6 months of pergolide therapy with some further improvement in vision. Patient 1 did have evidence of temporal lobe and brainstem compression on MRI, which resolved with tumor shrinkage.

Side effects.Five of the 22 patients reported side effects with pergolide therapy, which included mild headache (n = 2), nausea (n = 1), nasal stuffiness (n = 2), constipation (n = 1), and dizziness (n = 2). Liver function tests were monitored at baseline and periodically during the study, and no new liver function abnormalities developed on pergolide. Patient 17 had baseline liver function abnormalities due to chronic hepatitis B and cirrhosis and has not experienced worsening of his liver function during the 48 months of therapy, to date. No patient experienced clinically apparent pituitary hemorrhage during treatment or cerebrospinal fluid leaks. Two additional men followed in our Neuroendocrine Unit during the same time period as this study were begun on pergolide therapy for macroprolactinomas, but did not tolerate it due to side effects of nausea, fatigue, and dizziness. One of these patients had surgery, and the other is being treated medically with cabergoline.


    Discussion
 Top
 Introduction
 Case Report (Case 1)
 Report of Series
 Discussion
 References
 
Although the primary goal of treatment of microprolactinomas is normalization of PRL level and restoration of gonadal function, the goal of therapy for many macroprolactinomas is tumor shrinkage with relief of mass effect symptoms. Although surgery was once felt to be a necessary initial treatment for macroprolactinomas, the long-acting dopamine agonists are now considered as the primary therapy for these patients. Many studies of the use of BC and more recently with the more potent and longer-acting dopamine agonist cabergoline have shown that these medications reduce PRL levels, restore gonadal function, and induce tumor shrinkage in most patients with prolactinomas. Short-term studies have also demonstrated the effectiveness of pergolide in lowering PRL levels, but few studies have examined long-term outcome, and none have examined tumor shrinkage by MRI after pergolide therapy in macroprolactinomas. We have successfully treated many macroprolactinomas with pergolide as initial therapy before the availability of cabergoline. Although cabergoline, which is Food and Drug administration approved for this purpose, is emerging as first-line therapy for many patients, our experience has demonstrated the long-term efficacy and relative safety of pergolide therapy. The significantly lower cost of pergolide is also an important benefit for many patients. Therefore, there remains an important role for pergolide in the treatment of prolactinomas.

In our series of 22 patients with macroprolactinomas treated with pergolide, PRL levels normalized in 15 patients and approached normal in 2 others. Prior studies of pergolide therapy of both micro- and macroprolactinomas have shown high rates of PRL normalization; PRL levels were normalized in 37 of 41 (10), 17 of 18 (11), and 16 of 25 (12) subjects treated for periods from 6–24 months. The ability of pergolide and BC to lower PRL also seems to be similar (12, 13, 14), but some patients who have not responded well to BC have been reported to achieve better suppression of hyperprolactinemia with pergolide (15). Although the efficacy of pergolide and cabergoline have not been directly compared, in our series 68% of macroprolactinomas achieved full normalization of PRL levels, which is similar to the normalization rate of 73% reported recently for those treated with cabergoline (4).

Restoration of gonadal function is also an important goal of therapy of patients with prolactinomas. Pretreatment gonadal function in the male patients in our series was variable. For example, patient 1, who presented with impotence and normal testosterone levels, illustrates one extreme of the spectrum. The majority of the men, however, did have symptoms of hypogonadism and/or low pretreatment testosterone levels. On pergolide therapy alone, symptoms of hypogonadism improved significantly in 83% of men. Testosterone levels rose significantly in most men in our series, but normal levels were sustained in only 6 of 15 patients. Few studies have examined the effect of dopamine agonist therapy on normalization of testosterone levels in a large group of men with macroprolactinomas. In women, dopamine agonists clearly restore normal gonadal function in nearly all premenopausal women who tolerate the medication, but most such patients have microadenomas (3). In men, however, the rate of complete restoration of gonadal function with dopamine agonists alone is probably much less. In many studies the symptoms of hypogonadism are improved with dopamine agonist therapy. For example, symptoms of hypogonadism were improved in 50% (14) and 10 of 17 (10) men treated with pergolide, in 45% (14) of men treated with BC, and in 3 of 7 (16) and 8 of 8 (5) men treated with cabergoline for macroprolactinomas. However, improvement of symptoms is not always accompanied by normalization of testosterone. In our study, testosterone levels rose significantly in the majority of patients, but remained in the normal range in only 6 of 15 patients. Others have demonstrated a significant rise in testosterone in most men (1, 10, 17), but a normalization was achieved in only 7 of 12 (10) and 4 of 9 (1) with macroadenomas treated with either BC or pergolide. In a recent study with cabergoline, only two men with macroprolactinomas were not treated with testosterone supplements, and levels normalized in these two patients (4). It seems likely that the large tumors found in many men have permanently damaged gonadotropin function in addition to the reversible hypogonadism induced by hyperprolactinemia.

In addition to the failure to normalize testosterone levels in a number of patients, we also noted that two patients (1, 14) experienced a fall in testosterone levels after an initial rise. In patient 14, despite a peak testosterone level at 330 ng/mL, which is within normal limits, the most recent testosterone levels were low on more than one occasion despite continued tumor shrinkage and lack of evidence of other pituitary trophic hormone deficiency. Some fall in testosterone levels while on medications has been reported previously (10). Although the mechanism of the fall in testosterone despite PRL normalization is not clear, there is some evidence that in normal subjects dopamine may actually inhibit gonadotropin release. Some early studies reported a fall in LH with iv dopamine therapy in women (18) and with pergolide therapy in young men (19), although this was not reported with BC or lergotride (19). Whether this effect will be seen with other more potent and long-acting dopamine agonists is unknown and warrants investigation. In the four women in our series who were all believed to be postmenopausal restoration of gonadal status was not a goal of treatment.

Successful therapy of macroprolactinomas, especially those as large as the tumors in our series, requires reduction in tumor size with the goal of relief of symptoms of tumor mass effect. Therefore, because this had not previously been reported, we assessed tumor size in detail with serial MRIs in our patients treated with pergolide. We found that pergolide therapy resulted in significant tumor shrinkage in all 22 patients, in most cases with rapid relief of neurological deficits. In prior studies, in 10 of 13 (10), 6 of 9 (14), and 6 of 6 (11) reported cases, macroadenomas treated with pergolide shrunk significantly as demonstrated by computed tomography scanning. Numerous other smaller reports have demonstrated some tumor shrinkage with pergolide therapy (12, 13, 17, 20). The time course and degree of shrinkage were variable, and, in general, the amount of shrinkage did not always correlate with basal or percent fall in PRL level. As illustrated in case 1, PRL normalization in many cases was accompanied by tumor shrinkage. In others, complete PRL normalization was not always necessary for excellent tumor reduction, as shown in case 18. For the duration of our follow-up we have also observed that in most patients tumor shrinkage continues progressively with time.

In summary, our series demonstrates that pergolide is effective, safe, and generally well tolerated for the long-term treatment of macroprolactinomas. Rarely do side effects limit its use, and we have found that only approximately 8% of patients who are begun on pergolide will be intolerant of the medication. For those patients in whom pergolide is efficacious it can be continued safely for long periods of time. The shrinkage data provided by our series supports the use of pergolide for the long-term therapy of macroprolactinomas. Although for most newly diagnosed patients cabergoline is now first-line therapy in the United States, pergolide remains a viable option for the treatment of macroprolactinomas, particularly in men and postmenopausal women, in whom pregnancy is not of concern. It should be considered when other available therapies are not tolerated or when the cost of lifelong therapy with currently available medications is greater than patients can afford.

Received September 15, 1999.

Accepted October 11, 1999.


    References
 Top
 Introduction
 Case Report (Case 1)
 Report of Series
 Discussion
 References
 

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