Efficacy of cabergoline on rapid escalation of dose in men with macroprolactinomas

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1 Indian J Med Res 131, April 2010, pp Efficacy of cabergoline on rapid escalation of dose in men with macroprolactinomas A. Bhansali, R. Walia, P. Dutta, N. Khandelwal *, R. Sialy & S. Bhadada Departments of Endocrinology & * Radiodiagnosis, Postgraduate Institute of Medical Education & Research Chandigarh, India Received December 24, 2008 Background & objectives: Since cabergoline has a long half-life and sustained occupancy of dopamine (D 2 ) receptors in lactotrophs, its doses are slowly built up either monthly or two monthly. This possibly results in delayed normalization of serum prolactin and slow reduction in tumour size. This study was planned to assess the efficacy and safety of rapid escalation of cabergoline doses in men with macroprolactinomas. Materials: Fifteen consecutive men with macroprolactinomas underwent evaluation for anterior pituitary functions, visual fields, quality of life (QOL) score and magnetic resonance imaging (MRI), at baseline and after 6 months of cabergoline therapy. Serum prolactin and testosterone levels were assessed at monthly intervals. Cabergoline was started at a dosage of 0.5 mg twice per week and increased to 1.5 mg twice per week (3 mg ) by the third week, as 3 mg is usually considered as effective dose. Subsequent increase in doses was done as per protocol. Results: The mean age of patients at presentation was 31.7 ± 3.3 yr and duration of symptoms was 25.0 ± 3.6 months. Serum prolactin at baseline was ± μg/l with a tumour volume of 28.9 ± 8.3 cm 3. Eighty six per cent of the patients had visual field defects while 53 per cent had decreased visual acuity. The mean dose of cabergoline required was 3.2 mg/wk. Symptoms improved in majority (93%) of patients after four weeks of cabergoline therapy with a dramatic fall in serum prolactin by 99 per cent from ± to 46.9 ± 14.9 μg/l and it was normalized in 93 per cent of the patients by 8.2 wk. Improvement in visual field defects was noted in all but one, after one month and there was further improvement at 6 months. All patients had >25 per cent reduction in tumour size, and 73 per cent had > 50 per cent reduction after six months of cabergoline therapy. Basal circulating testosterone levels were low in 11 (73%) patients and started improving from first month of cabergoline therapy and became normal in around half of the patients after 6 months. No major side effects were observed requiring discontinuation of cabergoline therapy. Interpretation & conclusions: Our preliminary findings show that rapid build-up of cabergoline doses increases its efficacy as well as rapidity of response in terms clinical improvement, normalization of serum prolactin and gonadal functions and reduction in tumour size, without compromising its safety in men with macroprolactinomas. Further studies with a larger sample size and control group for comparison need to be done to confirm these findings. Key words Cabergoline - dose escalation - macroprolactinomas 530

2 bhansali et al: Rapid dose escalation of cabergoline in macroprolactinomas treatment 531 Prolactinomas are the most common functioning pituitary adenomas. However, these are relatively rare in men; more than 70 per cent of cases occur in women 1. These tumours are typically associated with ovulatory dysfunction and galactorrhoea in women and with hypogonadism in men. Macroprolactinomas usually cause symptoms of mass effect including headaches, visual field defects and hypopituitarism. Dopamine agonists are the first line of treatment in majority of patients with hyperprolactinemic disorders. Bromocriptine, introduced in 1970, is the original formulation against which newer dopamine agonists are compared 2. However, significant proportion of patients (up to 20%) have poor tolerability to the drug at therapeutic doses or have resistance to its effects 3. In addition, because of its short half-life, bromocriptine needs to be administered twice or thrice daily. Cabergoline, a newer dopamine agonist, has an advantage of once or twice weekly administration with minimal side-effects 4. Like bromocriptine, cabergoline is initiated at low doses and built-up slowly, though it is much better tolerated. It is apparent that doses and rapidity of dose escalation of dopamine agonists in treatment of hyperprolactinemia needs to be individualized 3. In patients with symptomatic chiasmal compression, urgent shrinkage of the tumour is important, whereas in patient with a microadenoma, a less rapid escalation of dopamine agonists may be required. The recommended schedule for escalation of cabergoline doses varies from monthly to two monthly increase with attaining the maximum effective dose of mg/wk 5,6. This relatively takes a longer time to normalize serum prolactin and reduction in tumour size is quite variable 4-6. However, clinical significance of rapid versus slow dose escalation of cabergoline has not been examined earlier. Therefore, this study was planned to assess efficacy and safety of rapid escalation of cabergoline doses in men with macroprolactinomas. Material & Methods Study design: Fifteen consecutive men with macroprolactinomas attending the Endocrine Clinic of the Nehru Hospital at Postgraduate Institute of Medical Education and Research, Chandigarh, India, during September 2004 to June 2006 were recruited for the study. A written informed consent was obtained from all these subjects. The study was approved by the Institute s Ethics Committee. Selection criteria: Post-pubertal men with macroprolactinomas (any tumour diameter > 10 mm) and serum prolactin level > 150 μg/l were recruited. None had any other systemic illness and they were not on any drug known to cause hyperprolactinemia. The patients were assessed at monthly intervals and at each visit, history and physical examination was carried out and investigated as per the following protocol during the six month study period. At the time of recruitment, at 0800 h, blood samples (10 ml) were drawn for the following investigations: haemogram, renal and liver function tests, and pooled samples ( two aliquots of similar volume at 20 min intervals) for serum prolactin, T3, T4, TSH, cortisol, LH, FSH and testosterone. Testosterone and prolactin levels were repeated at monthly intervals. Magnetic resonanes imaging (MRI) of the pituitary region was done at baseline and after six months of therapy. Tumour size was calculated by Dichiro s formula 7 ( п/6 x antero-posterior diameter x vertical diameter x transverse diameter). Decrease in tumor size of >25 per cent was considered as significant. Visual field defects were assessed on a 76 point scale with the Humphrey automated computerized perimeter, at 0, 1 and 6 months or in-between if any deterioration of vision was noticed. Quality of life (QOL) score was assessed at 0 and 6 months by questionnaire method 8. Serum prolactin (N,5-20 μg/l), T3(N, ng/ml), T4(N, μg/dl) and TSH(N mIU/l) levels were assessed by immunoradiometric/radioimmuno assay using commercial kits (Advia Centaur, Inc, Germany) with intra- and inter- assay coefficients of variation of < 8 per cent. Serum testosterone (N, 9-27 nmol/l) and cortisol (0800 h, nmol/l) were estimated with in-house radioimmunoassay 9. Serum LH, FSH were done with enzyme linked immunosorbent assay (ELISA) using commercial kits (Syntron Bio research, Inc., USA) with sensitivity of assay being 1.25 IU/l for both. The following criteria were used to define pituitary hormone deficiency. Serum T 4 level of <4 μg/dl with low or normal TSH was considered as secondary hypothyroidism, serum cortisol at 0800 h >350 nmol/l as adrenal sufficiency, <100 nmol/l as adrenal insufficiency and those with cortisol level between > nmol/l were considered to be in the grey zone and were supplemented only during stress 10,11. Serum testosterone level of <9 nmol/l was defined as hypogonadism. Treatment protocol: Tablet Cabergoline (Caberlin, Sun Pharmaceutical, Goa, India) was prescribed at night with food; first week : 0.5 mg twice per week, second week: 1.0 mg twice per week and third week: 1.5 mg

3 532 INDIAN J MED RES, April 2010 twice per week (e.g., Monday and Thursday), followed by continuation of the same dose till eighth week, as the usual effective dose (~3mg/wk) was already achieved by the third week. At the end of the eighth week, the dose was planned to be increased by 1.0 mg/wk, if the serum prolactin levels had not been normalized (<20 μg/l) by that time. Second hike in doses was planned at the end of sixteenth week if the serum prolactin levels remained above the normal range. Statistical analysis: ANOVA was used for repeated measures to evaluate the effect of cabergoline throughout the follow up. Various hormonal parameters pre- and post-therapy were analyzed using Wilcoxon s test. Statistical significance was set at 5 per cent. Correlations were performed by calculating the Spearman s coefficient, as the data were not normally distributed. Results The mean age of these patients at presentation was 31.7 ± 3.3 yr with a range of yr, and duration of symptoms 25.0 ± 3.6 months with a range of 1-36 months. All the patients registered completed the study without any drop-out. The presenting symptoms and signs are summarized in Table I. Serum prolactin at baseline was ± μg/l, with a range of μg/l. All patients had macroprolactinomas with a tumour volume of 29.0 ± 8.3 cm 3, varying from 1.3 to 92.2 cm 3. There was a correlation between tumour size and serum prolactin levels (r=0.60, P=0.05). The mean and maximum dose of cabergoline required was 3.2 and 4 mg per week respectively. All patients were euthyroid including one, who was on replacement with L-thyroxine therapy. One patient had 0800 h serum cortisol 50 nmol/l and received hydrocortisone replacement and 7 patients had 0800 h serum cortisol between > nmol/l and only one of them was symptomatic and thereby required cortisol replacement. The hormonal parameters at baseline are presented in Table II. Headache disappeared in 12 (80%) patients after one month and in all patients after 2 months of cabergoline therapy. It reappeared in one patient at four months of therapy because of pituitary apoplexy. Visual field defects and decreased visual acuity were present in 86 and 55 per cent of patients respectively and these markedly improved after one month of therapy and they further improved at 6 months. Libido improved in 12 (80%) patients after one month of therapy and in 93 per cent by 2 months of therapy. Table 1. Symptoms and signs at the time of presentation in patients with macroprolactinomas Symptoms No of patients ( % ) Headache 15 ( 100 ) Loss of libido 15 ( 100 ) Visual symptoms 13 ( 86 ) Erectile dysfunctions 10 ( 67 ) Gynaecomastia 7 ( 47 ) Galactorrhoea 3 ( 20 ) Decreased shaving frequency 3 ( 20 ) Infertility 3 ( 20 ) Arrested puberty 1 ( 7 ) Table II. Hormonal parameters and tumour volume at baseline and after 6 months of cabergoline therapy in patients with macroprolactinomas (n=15) Parameters Pre-therapy mean ±SEM baseline ± Post-therapy mean ±SEM 6 months 6.0 ±2.6 ** ( ) Prolactin (μg/l) (range) ( ) Testosterone (nmol/l) 7. 4 ± ±1.13 * LH(IU/l) 2.0 ± ± 0.46 FSH(IU/l) 1.4 ± ± 0.2 Tumour volume (cm 3 ) 29.0 ± ± 2.3 ** P * <0.005 ** < compared to pre-therapy Erectile dysfunctions improved in 8 of 10 patients after one month of therapy and in 9 of 10 after 2 months of therapy. One patient continued to have impaired libido and erectile dysfunctions, despite normalization of prolactin, but continued to have very low basal testosterone after 6 months of therapy. Galactorrhoea disappeared in 2 of the 3 patients after 3 months of therapy and in the remaining after 4 months of cabergoline therapy. All patients had a precipitous fall in serum prolactin after one month of cabergoline therapy to 46.9 ±14.9 μg/l, with a range of μg/l. The drop was statistically significant (P<0.001) with a mean percentage decrease of 99 per cent from baseline. In 6 patients, serum prolactin became normal ( 20 μg/l) at 1 month, in 9 by 2 months and in remaining six patients, it continued to decrease and became normal in all but one, in whom serum prolactin was 42.2 μg/l with >95 per cent decrease at 6 months. However, mean serum prolactin was normalized in 93 per cent of the patients by 8.2 wk. At six months, the serum prolactin was 6.0 ± 2.6 μg/l with a range from 1.00 to 42.2 μg/l. (Table II). There was a significant correlation between pretreatment tumour size and maximum required doses of cabergoline (R=0.52 P=0.04). Eleven patients had subnormal serum testosterone

4 bhansali et al: Rapid dose escalation of cabergoline in macroprolactinomas treatment 533 Fig. MR T1W image (a), coronal sections showing hyper-intense sellar mass with supra-sellar extension with a tumour volume of 9.3 cm3, follow up MR T1W image; (b) showing appreciable reduction (tumour volume 2.8 cm3, 71%) in sellar mass after six months of cabergoline therapy. (<9nmol/l) at baseline and it started improving from the first month in all patients and became normal at six months in 5 of the 11 patients after therapy. Serum testosterone levels took a longer time to attain normalcy as compared to the serum prolactin levels, except in one, in whom serum testosterone became normal despite raised levels of serum prolactin. However, there was no correlation found between increase in serum testosterone and decrease in serum prolactin levels at any point of time. Before therapy, all the patients had low normal basal levels of LH and FSH. After cabergoline therapy at six months, LH and FSH levels increased in all patients, though it could not reach statistical significance. Repeat MRI for pituitary after 6 months of therapy revealed a significant reduction in tumour size from 29.0 ± 8.3 to 5.8 ± 2.3 cm3 (P<0.001), accounting for a mean reduction of 66.8 per cent. All patients had > 25 per cent reduction in tumour size and 73 per cent had 50 per cent reduction after cabergoline therapy (Fig.). There was no new onset of hormone deficiency and serum cortisol at 0800 h became normal (>350 nmol/l) in seven of eight patients. No major side effects of cabergoline were observed requiring discontinuation of the therapy. One patient each complained of nausea and sleepiness, which subsided after 2 wk of therapy. One patient developed apoplexy after four months of therapy. He was managed conservatively with steroids and subsequently improved. Discussion The dose escalation of cabergoline in patients with macroprolactinomas in previous studies had varied from monthly to two monthly. A study by Biller et al5 showed normalization of serum prolactin in 73 per cent of the patients by mean duration of 19 wk with a mean dose of 1.82 mg with a monthly escalation. Similarly in other studies normalization of serum prolactin was delayed by wk with a monthly or three monthly escalation of cabergoline and the number of patients achieving normalization of serum prolactin did not increase further (50 to 83.3%) despite continued escalation in doses even by the end of the study period4-6,12-13 (Table III). In the present study, serum prolactin became normal in 93 per cent of the patients with a mean duration of 8.2 wk. The mean decrease in serum prolactin was 99 per cent by four weeks, however a similar decrease (93 to 99%) in prolactin was achieved in other studies with a time lag of 48 to 160 wk4-6,11,12. This supports the notion that rapid hike in doses of cabergoline decreases serum prolactin levels faster and it becomes normal in the majority of patients earlier. We observed a significant correlation between pre-treatment tumour size and the maximum required doses of cabergoline substantiating the fact that the larger tumours require higher doses to respond as compared to smaller macroprolactinomas. This observation has not been documented in previous studies. However, this may possibly be explained as larger tumours are likely to harbour more number of D2 receptors.

5 534 INDIAN J MED RES, April 2010 Authors Biller et al Colao et al * Ferrari et al Corsello et al Shimon et al No of patients Table III. Studies showing the efficacy of cabergoline in prolactinomas Cabergoline schedule mg once/wk ed by 0.25 mg after 4 wk followed by of 0.5 mg/ wk every 4 wk till PRL normalization mg once/wk, 0.5 mg twice/wk. Dose adjustment at 2 months depending upon PRL levels to 0.5 mg/wk and increased up till 10.5 mg/ wk mg thrice/wk. Dose adjustment at 3 months depending upon PRL levels mg twice/wk-1 st wk. 0.5 mg thrice/wk-2 nd wk. Dose adjustment at 2-3 months depending upon PRL levels Present study * mg twice/ wk,1.0 mg twice/wk-2nd wk,1.5 mg twice/wk-3rd wk. * Drug naïve patients PRL, prolactin Study Duration (months) Mean/ Median dose (mg) (median) (median) Mean duration to normalize PRL (wk) % decrease in prolactin (time in wk) % of patients in whom prolactin got normalized % of patients in whom tumour size decreased 25 % (mean % reduction) (48) (31) (104) ( 74 )??(?) (?) (160) (65) (101.2) (47) (66) There was a remarkable improvement in clinical symptomatology including headache, libido and potency after 4 wk of therapy. This is in contrast to the previous studies, where such improvement has been reported after 8-24 wk of therapy 6, Improvement in vision has been reported in per cent of patients in various series after a period of 4-24 wk In this study, all patients who had decrease in vision at baseline experienced improvement within 4 wk of therapy. The improvement in QOL score correlated with decrease in serum prolactin levels rather than increase in serum testosterone levels. This was observed in more than half (55%) of the patients, where decrease in serum prolactin levels were associated with improved libido and potency despite subnormal testosterone levels as shown by others also 6,17. Previous studies have shown mean tumour reduction of per cent over a duration of 3 months to 8 yr and the response rate increased with increasing duration of therapy 4-6, Mean tumour volume reduction by 66.8 per cent and tumour shrinkage of > 25 per cent in all the patients within 6 months in the present study supports the hypothesis of rapid build up of cabergoline therapy. The most commonly reported side effects with dopamine agonists are dizziness, headache, nausea and weakness 18,19. As it was likely that rapid escalation of cabergoline doses would have led to more frequent side effects. However, in the present study, there was no increased incidence of adverse drug reactions and none of the patients required discontinuation of therapy. One patient had an episode of apoplexy after four months of therapy, which is unlikely to be the result of rapid escalation of cabergoline doses, as a stable maintenance dose was achieved much earlier during the first month of therapy. The efficacy of cabergoline is dose related and determined by percentage of D 2 receptor occupancy and prolonged receptor affinity 20. The patients, who respond to increasing dosages of cabergoline, probably do so by

6 bhansali et al: Rapid dose escalation of cabergoline in macroprolactinomas treatment 535 an increased receptor occupancy with higher doses. It has been observed earlier that the patients, who do not respond initially, may remain resistant even after further increasing the doses 3. This is explained by the fact that in macroadenomas, there are sub-populations of tumour cells with D 2 receptors if remained unoccupied initially, may have a growth advantage and such tumours may not respond to increasing doses of cabergoline later on. This was evident in the present study by the fact that maximal number of patients achieved normalization of serum prolactin by eight weeks and this number did not increase further with escalation of cabergoline doses. However, the limitations of the present study are the smaller number of patients and lack of a control group who would have been treated with conventional treatment protocol, to compare the efficacy with the suggested protocol in the present study. In conclusion, rapid build-up of cabergoline doses increases its efficacy as well as rapidity of response without compromising its safety. The results are preliminary but promising and to substantiate these findings further larger and controlled studies are needed. Conflict of interest: There was no conflict of interest to declare. References 1. Mindermann T, Wilson CB. Age-related and gender related occurrence of pituitary adenomas. Clin Endocrinol 1994; 41 : Molitch ME, Elton RL, Blackwell RE, Cardwells B, Chang RJ, Jaffe R, et al. Bromocriptine as primary therapy for prolactin secreting macroadenomas : results of a prospective multicentre study. J Clin Endocrinol Metab 1985; 60 : Molitch ME. 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