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

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 3-3.5 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 eficacy 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 [micro]/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) (n/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 [micro]g/l), T3(N,0.6-1.8 ng/ml), T4(N,4.5-10.5 [micro]g/dl) and TSH(N0.5-5.5mIU/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, 350-550 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.sub.4] level of <4 [micro]g/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 insuficiency and those with cortisol level between >100-350 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 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 [micro]g/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 coeficient, as the data were not normally distributed.

Results

The mean age of these patients at presentation was 31.7 [+ or -] 3.3 yr with a range of 20-63 yr, and duration of symptoms 25.0 [+ or -] 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 6249.3 [+ or -] 3259.2 [micro]g/l, with a range of 186 -47904 (g/l. All patients had macroprolactinomas with a tumour volume of 29.0 [+ or -] 8.3 [cm.sup.3], varying from 1.3 to 92.2 [cm.sup.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 > 100-350 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.

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 [+ or -]14.9 [micro]g/l, with a range of 1.0-215 [micro]g/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 [micro]g/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 [micro]g/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 [+ or -] 2.6 [micro]g/l with a range from 1.00 to 42.2 [micro]g/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 (<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.

[FIGURE 1 OMITTED]

Repeat MRI for pituitary after 6 months of therapy revealed a significant reduction in tumour size from 29.0 [+ or -] 8.3 to 5.8 [+ or -] 2.3 [cm.sup.3] (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 [greater than or equal to] 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 al (5) 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 24-93 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 period (4-6,12-13) (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 wk (4-6,11,12). 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 [D.sub.2] receptors.

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 (6,12-16). Improvement in vision has been reported in 33-85 per cent of patients in various series after a period of 4-24 wk (12-16). 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 31-74 per cent over a duration of 3 months to 8 yr and the response rate increased with increasing duration of therapy (4-6,12-17). 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 eficacy of cabergoline is dose related and determined by percentage of [D.sub.2] receptor occupancy and prolonged receptor affinity (20). The patients, who respond to increasing dosages of cabergoline, probably do so by 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.sub.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 eficacy with the suggested protocol in the present study.

In conclusion, rapid build-up of cabergoline doses increases its eficacy 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.

Received December 24, 2008

References

(1.) Mindermann T, Wilson CB. Age-related and gender related occurrence of pituitary adenomas. Clin Endocrinol 1994; 41 : 359-64.

(2.) 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 : 698705.

(3.) Molitch ME. Medical management of prolactin secreting pituitary adenomas. Pituitary 2002; 5 : 55-65.

(4.) Corsello SM, Ubertini G, Altomare M, Lovicu RM, Migneco MG, Rota CA, et al. Giant prolactinomas in men: efficacy of caberoline treatment. Clin Endocrinol 2003; 58: 662-70.

(5.) Biller BMK, Molitch ME, Vance ML, Cannistraro KB, Davis KR, Simons JA, et al. Treatment of prolactin-secreting macroadenoma with once weekly dopamine agonist cabergoline. J Clin Endocrinol Metab 1996; 81 : 38-43.

(6.) Colao A, Vitale G, Cappabianca P, Briganti F, Ciccarelli A, De Rosa M, et al. Outcome of cabergoline treatment in men with prolactinoma: effects of a 24 months treatment on prolactin levels, tumor mass, recovery of pituitary function and semen analysis. J Clin Endocrinol Metab 2004; 89 : 1704-11.

(7.) Abbond CF. Louts ER. Diagnosis of pituitary tumors. Endocrinol Metab Clin N Am 1988: 17 : 241-74.

(8.) Heinemann LA, Moor C, Dinger JC, Stoehr D. Sensitivity and outcome measures of androgens; the AMS scale Health quality life outcomes. Health Qual Life Outcomes 2006; 4 : 23.

(9.) Dash RJ, England BG, Midgley AR Jr., Niswender GD. A specific, non-chromatographic radioiammunoassay for human plasma cortisol. Steroids 1975; 26 : 647-61.

(10.) Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: Guidelines for perioperative assessment and management. J Clin Endocrinol Metab 2002; 87 : 2745-50.

(11.) Hagg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of the pituitary--adrenal axis. Clin Endocrinol 1987; 44 : 141-6.

(12.) Ferrari CI, Abstract R, Bevan JS, Brabant G, Ciccarelli E, Mottta T, et al. Treatment of macroprolactinoma with cabergoline: a study of 85 patients. Clin Endocrinol 1997; 46 : 409-13.

(13.) Shimon I, Benbassat C, Hadani M. Effectiveness of long-term cabergoline treatment for giant prolactinoma: study of 12 men. Eur J Endocrinol 2007; 156 : 225-31.

(14.) De Rose M, Zarrilli S, Vitale G, Di somma C, Orio F, Tauchmanova L, et al. Six months treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence. J Clin Endocrinol Metab 2004; 89 : 621-5.

(15.) De Rosa M, Colao A, Di Sarno A, Ferone D, Landi ML, Zarrilli S, et al. Cabergoline treatment rapidly improves gonadal function in hyperprolactinemic males: a comparison with bromocriptine. Eur J Endocrinol 1998; 138 : 286-93.

(16.) Verhert J, Abs R, Maiter D, Vandeweghe M, Velkeniers B, Mockel J, et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 1999; 84 : 2518-22.

(17.) De Rose M, Ciccarelli A, Zarrilli S, Guerra E, Gaccione M, Disarno A, et al. The treatment with cabergoline for 24 months normalizes the quality of seminal fluid in hyperprolactinaemic males. Clin Endocrinol 2006; 64 : 307-13.

(18.) Page SR, Nussey SS. Cabergoline therapy of a large prolactinoma in a bromocriptine--intolerant patient. J Obstet Gynaecol 1989; 10 : 156-8.

(19.) Ciccarelli E, Camanni F. Diagnosis and drug therapy of prolactinoma. Drugs 1996; 51 : 954-65.

(20.) Ferrari C, Barbieri C, Caldava R, Music M, Codecasa F, Paracchi A, et al. Long lasting prolactin lowering effect of cabergoline a new dopamine agonist in hyperprolactinemic patients. J Clin Endocrinol Metab 1986; 63 : 941-5.

Reprint requests: Dr Anil Bhansali, Professor & Head, Department of Endocrinology, Postgraduate Institute of Medical Education & Research, Chandigarh 160 012, India e-mail: anilbhansali_endocrine@rediffmail.com

A. Bhansali, R. Walia, P. Dutta, N. Khandelwal *, R. Sialy & S. Bhadada

Departments of Endocrinology & * Radiodiagnosis, Postgraduate Institute of Medical Education & Research Chandigarh, India
Table I. 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 [+ or -] SEM
 baseline

Prolactin ([micro]g/l) 6249.3 [+ or -] 3259.2
(range) (186 - 47904)
Testosterone (nmol/l) 7. 4 [+ or -] 0.9
LH(IU/l) 2.0 [+ or -] 0 .4
FSH(IU/l) 1.4 [+ or -] 0.1
Tumour volume ([cm.sup.3]) 29.0 [+ or -] 8.3

Parameters Post-therapy
 mean [+ or -] SEM
 6 months

Prolactin ([micro]g/l) 6.0 [+ or -] 2.6 **
(range) (1.00 - 42.2)
Testosterone (nmol/l) 12.1 [+ or -]1.13 *
LH(IU/l) 2.4 [+ or -] 0.46
FSH(IU/l) 1.6 [+ or -] 0.2
Tumour volume ([cm.sup.3]) 5.8 [+ or -] 2.3 **

P * <0.005 ** < 0.001 compared to pre-therapy

Table III. Studies showing the efficacy of cabergoline in
prolactinomas

Authors No of Cabergoline
 patients schedule

Biller et al (5) 15 0.25mg once/wk [up arrow] ed
1996 by 0.25 mg after 4 wk
 followed by [up arrow] of 0.5 mg/
 wk every 4 wk till PRL
 normalization

Colao et al (6) 41 0.5 mg once/wk, 0.5 mg
2004 * twice/wk. Dose adjustment
 at 2 months depending
 upon PRL levels

Ferrari et al (12) 85 0.25 to 0.5 mg/wk and
1997 increased up till 10.5 mg/
 wk

Corsello et al (4) 10 0.5 mg thrice/wk. Dose
2003 adjustment at 3 months
 depending upon PRL
 levels

Shimon et al (13) 12 0.5 mg twice/wk-1st wk.
2007 0.5 mg thrice/wk-2nd wk.
 Dose adjustment at 2-3
 months depending upon
 PRL levels

Present study * 15 0.5 mg twice/ wk, 1.0 mg
 twice/wk-2nd wk, 1.5 mg
 twice/wk-3rd wk.

Authors Study Mean/ Mean % decrease
 Duration Median duration to in prolactin
 (months) dose (mg) normalize (time in
 PRL wk)
 (wk)

Biller et al (5) 12 1.82 18.9 93 (48)
1996 (mean)

Colao et al (6) 24 2.7 24 99(104)
2004 * (mean)

Ferrari et al (12) 15 1 ? ?(?)
1997 (median)

Corsello et al (4) 39 3.3 54.4 98(160)
2003 (mean)

Shimon et al (13) 108 3.4 92.8 99.8 (101.2)
2007 (median)

Present study * 6 3.2 8 98
 (mean)

Authors % of patients % of patients in
 in whom whom tumour size
 prolactin decreased [greater
 got than or equal to]
 normalized 25 % (mean %
 reduction)

Biller et al (5) 73 73
1996 (31)

Colao et al (6) 75.6 100
2004 * (74)

Ferrari et al (12) 61.2 61.1
1997 (?)

Corsello et al (4) 50 90
2003 (65)

Shimon et al (13) 83.3 75
2007 (47)

Present study * 93 100
 (66)

* Drug naive patients
PRL, prolactin
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Author:Bhansali, A.; Walia, R.; Dutta, P.; Khandelwal, N.; Sialy, R.; Bhadada, S.
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Apr 1, 2010
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