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Annales d'Endocrinologie
Vol 63, N° 6-C1  - décembre 2002
pp. 524-531
Doi : AE-12-2002-63-6-0003-4266-101019-ART5
Efficacy and safety of bromocriptine in the treatment of macroprolactinomas
 

O. Essaïs [1], R. Bouguerra [2], J. Hamzaoui [1], Z. Marrakchi [2], S. Hadjri [2], S. Chamakhi [2], B. Zidi [1], C. Ben Slama [2]
[1]  Department of Endocrinology, Hôpital Militaire de Tunis, Montfleury-Tunis, Tunisie.
[2]  Department of Endocrinology and Nutrition, Institut National de Nutrition, Tunis, Tunisie.

Tirés à part : O. Essaïs [2]

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Efficacité et innocuité de la bromocriptine dans le traitement des macroprolactinomes

Afin d'évaluer l'efficacité de la bromocriptine (BRC) comme traitement de première intention dans les macroprolactinomes à extension suprasellaire, nous avons mené une étude rétrospective, multicentrique ayant inclus 29 dossiers. Notre série comporte 19 femmes et 10 hommes. L'âge moyen est de 33 ans. Un hypogonadisme était present chez 94 % des femmes et 57 % des hommes, alors que le syndrome tumoral (à type de céphalées et/ou troubles visuels) prédomine chez l'homme. La prolactinémie (PRL) initiale est de 1 501 ng /ml : 202 ng/ml chez les femmes (extrême : 70-478 ng/ml) et 3 870 ng/ml chez les hommes (extrême : 100-20 476 ng/ml). Elle est corrélée au volume tumoral. 25 patients ont été traités initialement par BRC à la dose moyenne de 9,7 mg/j (13 mg/j chez les hommes et 8 mg/j chez les femmes). L'évolution est marquée par la réduction puis la normalisation de la PRL chez tous les hommes et chez 17/19 femmes en une durée moyenne de 6 mois (3-72 mois). Une réduction de plus de 50 % du volume tumoral est obtenue dans 18/29 cas et est associée à une selle turcique vide dans 5 cas, alors qu'une réduction de moins de 50 % est observée dans 11 cas. La réponse radiologique cumulative à la BRC augmente avec le temps. Il apparaît donc qu'un traitement prolongé par BRC est bien toléré et efficace dans les macroprolacti nomes.

Abstract
Efficacy and safety of bromocriptine in the treatment of macroprolactinomas

To assess the effectiveness of bromocriptine (BRC) as primary therapy in reducing the size of PRL-secreting macroadenomas with extra-sellar extension, we conducted a multicenter study in 29 patients without prior radiotherapy. Clinical presentation, response to medical treatment and long term follow-up of 29 patients with macroprolactinoma (pituitary mass more than 10 mm in diameter) were analysed. There were 19 women for 10 men. Mean age was 33 years. An hypogonadism was present in 94 % of women vs 57 % for men. Headaches and or visual abnormalities were present in 68 % of women vs 90 % of men. The mean basal serum prolactin level before treatment was 1 501 ng/ml : 202 ng/ml for women (range : 70-478 ng/ml) and 3 870 ng/ml for men (range : 100-20 476 ng/ml) and was correlated to tumoral size. 25 patients were treated with BRC as primary therapy with a mean dose of 9,7 mg/day (13 mg/day in men and 8 mg/day in women). BRC no malized serum PRL levels in all men and in 17/19 women over a mean period of 6 months, ranging from 3 to 72 months in both sexes. Tumor size was reduced by more than 50 % in 18/29 patients (62 %) with secondary empty sella in 5 patients and by less than 50 % in 11 patients. Visual field improved in most of the patients in whom it was initially abnormal. Reduction in size was quite fast in most of patients but slower in some of them. The cumulative radiological response to BRC increased with time. Therefore, it appears that prolonged medical therapy is effective and safe in macroprolactinomas.


Mots clés : Prolactinome , agoniste dopamine , bromocriptine , volume tumoral

Keywords: Prolactinoma , agonist dopamine , bromocriptine , tumor size


Introduction

The surgical approach of macroprolactinomas was less successful than in microadenomas (< 10 mm) and only unfrequently does the serum prolactin activity return to normal. Even if normal Prolactin levels are achieved by surgery initially, hyperprolactinemia seems to recur within few years in most patients with macroprolactinomas (in [15]).

Because macroprolactinomas were cured in less than 30 % of cases in the very best neurosurgical hands, near all authors agree that medical therapy is the first line of treatment [25].

Recently new dopamine agonists were introduced and they are highly effective in reducing tumor size, prolactin levels, restoration of pituitary functions and prevention of recurrence in prolactinomas. But they are not currently available in our country and too expensive comparing to Bromocriptine. So we conducted a descriptive multicentric study in 29 patients with macroprolactinoma to estimate the effectiveness of bromocriptine as primary therapy, and to assess its place among the newer drugs.

Subjects and methods

It was a retrospective study made between 1990 and 2000 including 29 patients with macroprolactine – secreting pituitary adenomas and followed in five medical centers.

The following criteria for patient selection were used :

  • All of them had at least two serum prolactin measurement over 50 ng/ml.
  • They had radiological evidence of macroadenoma with a pituitary mass measuring more than 10 mm in diameter.
  • There was no endocrinological evidence of mixed tumor as secreting GH or ACTH. They had no primary hypothyroidism and used no medication known to elevate prolactin.
  • The patients had no prior pituitary irradiation.

The main characteristics of pretreatment patients were shown in tableau 1.

In women, galactorrhea was present in 13/19 cases and menstrual disturbances or amenorrhea were noted in all cases. In three cases, the cause of consultation was delayed puberty. In men, gynecomastia and/or galactorrhea were present in 4 cases/10, decreased libido and/or impotence in 8 cases/10. Hypofertility was the cause of consultation in 3 cases/19 in women and in 1 case/10 in men.

Headaches and/or visual field disturbances were observed in 68 % in women vs 90 % in men.

Initial hormonal measurements were performed using standard RIA techniques or immunoradiometric assay methods exploring pituitary function. The upper limit for PRL was between 15 and 20 ng/ml.

Radiological assessment of the tumors was performed using high resolution MRI (magnetic resonance imaging) or CT (computed tomography) scans. Tumor size was evaluated using the maximum cranio-caudal diameter obtained at coronal sections. Tumors were graded on the degree of extra- sellar extension and the overall size of the tumor. Radiological studies were repeated every 6 to 12 months. The reduction in tumor size was variable and we divided the response into those with no reduction in tumor size and those with up to 50 % reduction.

Assessement of visual field defects by Goldmann- Friedmann perimetry was performed at baseline in 22 of 29 patients.

All patients were initially treated by BRC, doses were risen gradually until normal serum PRL level was achieved. Doses varied from 2,5 mg/day to 20 mg/day.

Four patients underwent transsphenoidal pituitary surgery before they referred to us. And in one case, surgery followed medical resistance to BRC, Quinagolide and Cabergoline. Resistance to bromocriptine was defined by persistence of high level of serum prolactin under regular BRC therapy over 15 mg/day for at least 3 months.

All patients were followed for a mean duration of 35.7 months (range : 3-228 months) and were represented in tableau 2, tableau 3.

Statistical analyses were performed by analysis of variance and the Kruskal-Wallist test. The unpaired Khi 2 test was used to compare percentages, and p was significant if < 0.05. In certain results serum prolactin levels were expressed in Log PRL to facilitate comparison.

Results
Pretreatment data

The mean age at diagnosis was 33 years : 42 ± 15 years in men and 28 ± 8 years in women (p = 0.008). Mean duration of symptoms before diagnosis was 39 months (28 ± 45 months in men and 43 ± 33 months in women) but this difference was not significant. Pretreatment mean serum prolactin level was 1 501 ng/ml (extremes : 70-20 476 ng/ml) and it was significantly less in women than in men : 186 ± 115 ng/ml (range : 70-478 ng/ml) vs 3 870 ± 6 724 ng/ml (range : 100-20 476 ng/ml). Mean size of macroadenomas was 20 mm and they were larger in men than in women : 25 ± 9 mm in male vs 17 ± 6 mm in female (p = 0.03). In both men and women serum prolactin level correlated significantly with tumor size (p = 0.02) figure 1. Extra sellar extension was present in 68.5 % in female vs 80 % in male and was associated to visual field defects in 31 % of female vs 44 % of male.

Response to Bromocriptine therapy

Mean duration of treatment was 30 ± 27 months (range : 1 – 120 m). Mean dose of BRC was 9,7 ± 5,3 mg/day. Doses needed of BRC were correlated to basal prolactin, and women received lower doses of BRC than men : 8 ± 5 vs 13 ± 6 mg/day. (p = 0.008) tableau 4.

Menses returned in 16/19 F and normal libido was restored in all men. 93 % of our patients (27/29) had lowered their serum prolactin level.

During the first three months of BRC therapy, PRL levels fell in all patients, and the mean serum prolactin level was 136 ng/ml with a mean dose of BRC of 7 mg/day, serum PRL level was 34.8 ng/ml at six months, and nadir serum PRL levels were reached in the nineth month of treatment (5 ng/ml ) with a mean dose of 8 mg/d figure 2. The percentage reduction of PRL was 62.8 % (± 54). Once serum prolactin levels were lowered, they tended to stabilize figure 3.

A complete shrinkage of the tumor or a reduction in its size of more than 50 % were noted in 43 % and 24 % of cases respectively. Whereas a regression of less than 50 % in tumor size was seen only in 33 % (19 % reduction of less than 25 %). Under treatment no development of tumor size was observed. Partial empty sella was seen in 5 patients and was considered as tumor shrinkage. The tumoral size response seemed to be better in women than in men at the opposite of PRL response. During the first year of treatment, reduction of tumoral size seems to be better in men than in women : 57 % of men had a shrinkage or a reduction of tumoral size greater than 50 % vs 33 % of women. Percentage reduction of tumoral size was unchanged during therapy in men while it increased gradually in women with time. Over 36 months of treatment, 75 % of women showed a reduction in tumor size greater than 50 % whereas, only 57 % of men showed such a reduction. The cumulative radiological response to BRC seemed to be associated to a longer duration of treatment tableau 5. Actually, a tumoral reduction superior to 50 % or a shrinkage was seen in 38 % after one year of treatment, rose to 43 % after two years, and to 67 % after three years or over figure 4.

In our line of patients, side effects of BRC were observed in three patients (10 %). In patients n 9 and 15 we were forced to discontinue the drug momentarily and in patient n 26 we reduced BRC doses.

Discussion

The objectives of our study were to evaluate clinical, hormonal and neuro-radiological characteristics of 29 macroprolactinomas in men and women, and their responses to BRC. In our line of patients there were several sex-related differences. Men tended to be older (p = 0.008), had higher basal PRL levels (p = 0.02) and larger adenomas than women (p = 0.03). Age at presentation was significantly higher in men than in women (p = 0.008). Endocrine syndrome was predominant in women. Most signs were represented by amenorrhea and/or galactorrhea. In men, gynecomastia was noted in 36 % compared to 10 % in some series [3]. Gonadal function was altered in 80 % of our patients while impaired thyreotropine and corticotropine reserves were seen in 5.5 % and 10.5 % respectively secondary to mass compression. A longer delay in diagnosis was observed in women than in men. It may be attributed probably to the importance of tumoral syndrome in men, and that women tend to neglect initially their symptoms. Actually many authors agree that there is no correlation between tumor size and duration of disease, and that differences in serum PRL levels and tumoral size between men and women should not be due to precocity of diagnosis but to a greater proliferative potential of the tumors and more invasive growth among men [11] [23].

Apoplexy was rare in the course of macroprolactinomas. In our series it was clinically evident in one patient (n 16) and silent in three others. Diagnosis was then made on MRI imaging. Different data showed that only 6.8 % of patients with macroadenomas had symptomatic pituitary necrosis during evolution, whereas histological data of autopsy revealed necrosis in 16.6 % [4], more frequently apoplexy was partial and only diagnosed on radiologic imaging [12].

Patient n 16 was a 30-year-old pregnant woman. She presented in emergency with clinical signs of apoplexy. Pituitary magnetic resonance imaging had confirmed the diagnosis.

She was operated in emergency by transsphenoidal approach. Postoperative data showed an improvement of her vision. Pregnancy continued without incidents. It is well established that surgical removal was successful in restoring visual abnormalities but for many authors decompression of the optic nerves and chiasm may occur in non-pregnant women by medical therapy [7].

Bromocriptine was the main dopamine-agonist agent used in our patients. Doses varied with mean prolactin and tumor size. So that men required higher doses of BRC.

PRL levels decreased in quite all patients after the first three months of treatment. Tumoral size reduction appeared also towards the third month of BRC therapy and was sustained all over the period of treatment. Tumor size reduction was greater in women than in men : 75 % of women showed a reduction over 50 % in tumoral size or a shrinkage, vs 57 % of men after 36 months of treatment. It seems that PRL men's response to treatment was quicker and more spectacular. Indeed, a higher pretreatment serum PRL level is not a predictive factor for response to treatment [24]. There was no correlation between tumoral size reduction and serum PRL levels [5] [13] [14] [17]. Additionally, Molitch found that tumor size reduction did not correlate with nadir PRL or percent fall in PRL level. However, a reduction in prolactin levels always preceeded any detectable change in tumor size [19] [20]. In contrast some authors found that nadir prolactin level was the strongest predictor of tumor reduction [8]. An interesting finding of our study was the wide variation in the timing of tumoral size reduction. It was reported that shrinkage may occur in the space of hours or days or weeks [20]or may take months or years [2]. In our line of patients men's response in tumoral size was initally better during the first year of treatment, while women's response increased with time. Cumulative radiologic results showed that macroprolactinomas experienced shrinkage progressively with time in both men and women. In agreement with many authors we insisted on the importance of treatment duration : when it was longer than 1 year, the percentage of tumors displaying a reduction in tumor size was higher [1] [13].

We can not predict whether some of our patients will be cured but we believe that for most of them, dopamine-agonist treatment will be life-long. We found as many authors [2] [10] [18]that BRC was efficient in the treatment of both hyperprolactinemia and in reducing tumor size, but we observed two female cases of macroprolactinoma “resistant” to BRC with delayed puberty (n 12-13). In patient n 13, serum prolactin remained elevated despite BRC, Quinagolide and Cabergoline therapy while adenoma showed a complete shrinkage after two years of treatment. Patient n 12 underwent selective transsphenoidal surgery. Six months later, recurrence of hyperprolactinemia happened and medical treatment (Cabergoline) was conducted again despite normal postoperative imaging. These two cases illustrated the difficulties in the treatment of macroadenomas when approaching the puberty [6] [10]and instead of speaking about resistance to bromocriptine it was in fact a dissociation : the mechanism for this dichotomy in response is unknown [19]. But if this figure continues, a malignant carcinoma will be suspected. Only 18 cases were described, and only metastatic lesions will confirm malignity [16] [21] [22].

BRC was well tolerated and side effects were rare (10 %). We reported particularly, severe psychiatric symptoms in two male patients (n 24-26). Those troubles appeared under 15 mg/day of BRC and disappeared when reducing doses at 5 mg/day.

It remains that the long-term efficacy of BRC is limited by the two to four times daily ingestion which may represent the most important factor to adhere to the prescribed therapeutic regimen. Therefore alternative medical therapies were wide used in the industrialised countries such as Cabergoline and Quinagolide.

Quinagolide, a non-ergot dopaminergic agonist, is a useful tool in the treatment of macroprolactinomas. Indeed a normalisation of PRL levels and a significant tumoral reduction were obtained in 56 % to 65 % of patients under this treatment. Further more it's interesting to presribe it in case of resistance to BRC [24].

Patients under Pergolide achieved full normalisation of PRL levels in 68 % of cases [13].

Finally, Cabergoline is the longest acting of all oral dopamine-agonists. It's half-life is prolonged to 7 days and allows a once-weekly administation. So that compliance to the treatment will be easier. Under this treatment patients achieved a reduction in tumor size and PRL levels declined to normal in 73 % of cases [2]. An interesting finding was its effectiveness in patients with prolacinomas resistant to both BRC or Quinagolide [9].

Conclusion

Tumor volume reduction did not correlate with PRL reduction and there was a time dissociation between PRL response and tumor reduction. Some prolactinomas may take months or years to shrink. So, prolonged medical therapy with Bromocriptine is effective and safe in the majority of macroprolactinomas. Although it was introduced into clinical research 26 years ago it remains the first and cheapest medication for men and women with macroprolactinomas in our country. The new dopamine-agonists are a good alternative in the treatment of macroprolactinomas with a better compliance and reduced side effects.

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The authors wish to thank Mr Abdelwahed Azib for expert language assistance.





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