| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
Neuroendocrine Unit, Hospital das Clínicas, University of São Paulo Medical School, 05403-000, São Paulo, Brazil
Address all correspondence and requests for reprints to: Marcello D. Bronstein, M.D., Division of Endocrinology and Metabolism, Hospital DAS Clinicas, Faculdade de Medicina DA USP, R. Dr. Eneas de Carvalho Aguiar, 255, 7°. Andar Sala 7037, São Paulo, SP, Brazil. E-mail: . mdbronstein{at}uol.com.br
Abstract
Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas. However, the major disadvantage is the need for prolonged therapy. We retrospectively studied 131 patients [62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)], who achieved serum prolactin (PRL) normalization during BRC use. Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery. Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal. The median time of BRC use was 47 months. There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis. BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate. A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.
MEDICAL TREATMENT with bromocriptine (BRC) and other dopamine (DA) agonist drugs such as cabergoline and quinagolide are considered the first choice therapy for both microprolactinomas (MICs) and macroprolactinomas (MACs) (1). Clinical and neurological improvement is often obtained with serum prolactin (PRL) normalization in 70–80% of patients, and tumor shrinkage in about 80% of MACs. However, one of the drawbacks is the need for long-term therapy. In fact, BRC discontinuation leads to recurrence of hyperprolactinemia in most patients and, at least after short-term use, to tumor regrowth (1, 2, 3). Nonetheless, there are some studies that show maintenance of normoprolactinemia and absence of adenoma reexpansion after BRC withdrawal in patients on long-term treatment for prolactinomas (4, 5, 6, 7, 8, 9). However, none of these studies assessed the presence of variables that could predict PRL normalization after BRC discontinuation.
The aim of this study is to evaluate the effect of BRC withdrawal in a large cohort of patients with prolactinomas and to look for variables that could potentially predict the outcome.
Subjects and Methods
Patients
Three hundred fifty patients (280 females and 70 males, 10–70 yr of age) with prolactinomas (189 microadenomas, 161 macroadenomas), followed up at the Neuroendocrine Unit of University of São Paulo Medical School, from 1978 to 2000, were retrospectively evaluated, having as end point the persistence of normoprolactinemia after BRC discontinuation. From this cohort, 301 patients were primarily treated with BRC (median dose, 5 mg; range, 1.25–25 mg), and 114 patients underwent pituitary surgery: 49 cases as the first therapeutic approach, and 65 cases because of the lack of serum PRL normalization during primary BRC use (median dose, 7.5 mg; range, 1.25–20 mg). Seventy-two patients who underwent surgery without serum PRL normalization received BRC (median dose, 7.94 mg; range, 0.6–25 mg). The dose was progressively reduced and suspended in subjects who achieved normoprolactinemia. Patients were divided in 2 groups, according to persistence (group 1) or absence (group 2) of normoprolactinemia after BRC discontinuation, and the groups were compared regarding age, gender, tumor size, pretreatment serum PRL levels, BRC initial dose, treatment length, pregnancy during therapy, and previous surgery and radiotherapy (Tables 1
and 2).
|
|
).
|
Computed tomography and/or magnetic resonance imaging scans were performed on all patients before treatment. In patients with MACs, tumor size was reassessed during and after BRC administration. Because this is a retrospective review, imaging studies after DA agonist treatment were not available in all patients with MICs.
Hormone assays
Serum PRL levels were measured by commercial kits: RIA from 1978 to 1992 (normal value < 20 µg/liter), and immunoradiometric assay (normal value, women: 2.5–14.5 µg/liter; men: 2.3–11.5 µg/liter) thereafter.
Statistical analysis
Univariate analysis was performed through Student’s t test to evaluate the influence of age, initial PRL levels, BRC initial dose, and period of BRC use on the persistence of normoprolactinemia. The chi-square test or Fisher’s exact test was used to evaluate the influence of gender, tumor size, pregnancy, surgery, and radiotherapy. Multivariate analysis, which searched for possible predictor factors, was performed by logistic regression analysis, only for P value less than 0.25 in univariate analysis and stepwise selection process.
Results
Twenty-seven of 131 patients with prolactinomas (20.6%), who attained normal PRL levels during BRC use, persisted with normoprolactinemia after drug withdrawal (25.8% MICs and 15.9% MACs) during a follow-up time of 3–240 months (median, 44 months) without BRC. No tumor reexpansion was observed in patients with MACs. Because MICs were not routinely reevaluated by image, any changes in size during and after BRC treatment in this group could not be assessed.
Patients from group 1 and group 2 used BRC during a median time of 47 and 50 months, respectively. None of the variables studied (gender, age, tumor size, pretreatment serum PRL levels, BRC initial dose, treatment period) predicted the persistence of normoprolactinemia after drug withdrawal. Even pregnancy, previous surgery, and radiotherapy did not influence the outcome after BRC suspension (Table 2
). Because the percentage of radiotherapy between groups 1 and 2 seemed to show some (although not significant) difference, data were reassessed after excluding patients who underwent radiotherapy. Three patients were excluded from group 1 (now totaling 24 patients) and 4 from group 2 (now totaling 100 patients). Once again, the comparison between these 2 groups did not show any statistically significant difference.
Discussion
In this retrospective study involving a large cohort of patients with prolactinomas treated with BRC, we were able to demonstrate that about one quarter of them persisted with normoprolactinemia after drug withdrawal.
DA agonist drugs are potent ligands of the G protein-type pituitary D2 receptor, negatively coupled to adenylate cyclase (10). Its activation ultimately inhibits PRL gene expression and lactotroph metabolism, leading to reduction in PRL synthesis and release, as well as to tumor shrinkage (10, 11, 12).
As far as tumor regrowth after BRC discontinuation is concerned, there are clear differences according to treatment length. Prolactinomas are more susceptible to regrowth after a short course of treatment, considered as being less than 1-yr therapy (1, 2, 3, 12).
Concerning long-term therapy with BRC, there is evidence of persistence of normoprolactinemia after drug withdrawal, but evaluations in large cohorts of patients are limited. The percentage of patients that remained normoprolactinemic after drug interruption is quite variable in the literature, ranging from 6.6–37.5% (4, 5, 6, 7, 8). There is some evidence that recurrence of hyperprolactinemia occurs mainly shortly after drug withdrawal: Zarate et al. (9) observed that 6 of 16 women remained normoprolactinemic after drug withdrawal, and recurrence of hyperprolactinemia occurred within 3 months of observation in the remaining 10 patients. Similarly, Cunnah et al. (13) observed that 15–20% of patients with hyperprolactinemia maintained normal serum PRL levels after BRC suspension; and usually, when recurrence occurred, it happened within 2 months of the drug withdrawal. However, the maintenance of normal PRL levels after short-term drug withdrawal may not represent true recurrence but, rather, a long-lasting residual effect of BRC. Therefore, albeit arbitrary, a follow-up period of at least 3 months of normoprolactinemia was used to include patients in group 1.
Our data are in agreement with literature reports (Table 3). Nonetheless, an important question is raised: why do long-term findings differ from short-term ones?
|
Gen et al. (15) suggested a cytocidal effect of prolonged treatment with BRC on tumor cells. van't Verlaat et al. (6) observed reduction of tumor nests and also acellular spaces. They also speculate that BRC might have a cytostatic effect related to short-term therapy, and a cytocidal one to long-term therapy, and suggest that this finding may explain the maintenance of normoprolactinemia after drug withdrawal.
Although these findings may explain the normoprolactinemia after BRC discontinuation, there are other factors, besides the drug use, that could influence prolactinomas evolution. Jeffcoate et al. (16) followed women with prolactinomas for 15 yr and found that the ones that became pregnant had higher percentages of remission (35% vs. 14%). Several studies showed PRL decrease (or even normalization) after pregnancies in women with prolactinomas treated with BRC. Radiotherapy might be another factor. Nabarro et al. (17) and Grossman et al. (18) showed that 4 of 15 patients and 8 of 27 patients with prolactinomas, respectively, achieved normal PRL levels after being treated with conventional radiotherapy. However, we were not able to find any statistically significant influence of these factors concerning maintenance of normoprolactinemia after drug withdrawal in our cases.
Menopause could be an additional factor influencing the reduction of serum PRL. Karunakaran et al. (19), when studying women with MICs, found that the ones past menopause had a significant chance of achieving normal PRL levels. We did not study the effect of menopause in prolactinomas evolution. However, the mean (±SD) age of the patients studied was 34 (±9.4) yr in group 1 and 39 (±12.5) yr in group 2, which would suggest that menopause was not a major factor influencing our results. Furthermore, there were only 2 patients older than 50 yr in group 1 (10%), and 13 patients in group 2 (17%), that would negatively influence our results, and even then there was no difference between the 2 groups.
Another factor that may influence remission of prolactinomas is their natural history. Koppelman et al. (20) studied 25 women with untreated hyperprolactinemia (18 microadenomas, 7 macroadenomas) for a mean period of 11.3 yr (mean initial PRL levels, 225 µg/liter). Seven (1 macroadenoma) of 22 patients with amenorrhea resumed menses spontaneously. Galactorrhea resolved completely in 8 of 19 patients. Only 1 had a slight progression of sellar abnormality. At the reevaluation, mean PRL levels decreased to 155 µg/liter. Schlechte et al. (21) followed 30 women with hyperprolactinemia (18 with normal pituitary image or empty sella) without treatment (average of 5.2 yr), and 35% showed improvement in clinical symptoms. Six of 30 women had increased PRL levels, 14 presented no changes, and 10 had a decrease (with PRL normalization in 6). Martin et al. (22) studied 41 patients with so-called idiopathic hyperprolactinemia, for a year, and found that 83% of patients had PRL levels unchanged (or even decreased) and 34% presented normalization of PRL levels. Sisam et al. (23) found that nearly 55% of 38 patients with MICs had normalization of PRL levels, and there was no tumor growth during a mean follow-up period of 31months. Jeffcoate et al. (16), following women with hyperprolactinemia (macroadenomas were excluded) for 15 yr, found that 33% of them presented normalization of PRL levels without any treatment. These data indicate that natural history has an important role in the outcome of prolactinomas. However, the mechanisms involved are yet to be clarified.
The evolution of one of our patients is depicted in Fig. 2. This 14-yr-old girl presented with an intra- and suprasellar mass and pretreatment PRL levels at 108 µg/liter; PRL normalization, along with tumor shrinkage, was observed during BRC treatment. The hormone remained at normal levels, and the pituitary image was near normal at 16 months after BRC withdrawal. Although we cannot rule out BRC influence, the brightness observed in T1-weighted image without contrast (Fig. 2A) is highly suggestive of hemorrhage within the tumor. Therefore, a subclinical pituitary apoplexy before medical treatment could be a major factor involved in PRL normalization.
|
We suggest that a gradual drug dose reduction should be attempted, along with the monitoring of PRL levels in patients under DA agonists who present normalization of PRL levels. To avoid unnecessary treatment, drug withdrawal can be attempted in this group of patients, with periodical reassessments.
Acknowledgments
We thank Sonia Strong for English revision.
Footnotes
Abbreviations: BRC, Bromocriptine; DA, dopamine; MAC, macroprolactinoma; MIC, microprolactinoma; PRL, prolactin.
Received October 22, 2001.
Accepted April 24, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  A. Klibanski Dopamine Agonist Therapy in Prolactinomas: When Can Treatment Be Discontinued? J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2247 - 2249. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Schlechte Long-Term Management of Prolactinomas J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2861 - 2865. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Gillam, M. E. Molitch, G. Lombardi, and A. Colao Advances in the Treatment of Prolactinomas Endocr. Rev., August 1, 2006; 27(5): 485 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Colao, A. Di Sarno, P. Cappabianca, C. Di Somma, R. Pivonello, and G. Lombardi Withdrawal of Long-Term Cabergoline Therapy for Tumoral and Nontumoral Hyperprolactinemia N. Engl. J. Med., November 20, 2003; 349(21): 2023 - 2033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Schlechte Prolactinoma N. Engl. J. Med., November 20, 2003; 349(21): 2035 - 2041. [Full Text] [PDF]
|
|
|
|
 |
|
 O. Serri, C. L. Chik, E. Ur, and S. Ezzat Diagnosis and management of hyperprolactinemia Can. Med. Assoc. J., September 16, 2003; 169(6): 575 - 581. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
