Journal of Cancer Therapy, 2010, 1, 214-218
doi:10.4236/jct.2010.14033 Published Online December 2010 (
Copyright © 2010 SciRes. JCT
Combined Treatment with Buserelin+Cabergoline
in Patient with Prostate Cancer and Pituitary
Mihály Gervain1, Erika Vörös 2, Andor H. Molnár 3, Gyöngyi Karcsú-Kis3, Ferenc László3
Ferenc A. László3
1Department of Urology, City Hospital, Orosháza, Hungary; 2 Euromedic Diagnostics, Szeged, Hungary; 3 Department of Physiology,
Anatomy and Neurosciences, University of Szeged, Szeged, Hungary.
Received June 28th, 2010; revised August 1st, 2010; accepted September 5th, 2010.
Twelve years following hemicolectomy for colon adenocarcinoma, a 75-year-old patient with prostate cancer was
treated for 4 weeks with the antiandrogen nilutamide and then with the long-acting GnRH agonist buserelin. The serum
testosterone and p rostate-specific antigen levels had decreased dramatica lly after 3 months of treatment. After 2 years
of buserelin administration, the hormonal state was examined. Serum estradiol, testosterone, DHEA, DHEAS, FSH and
LH levels proved to be suppressed, but the serum PRL concentration was extremely high (3 365 mIU/l). The pituitary
MRI revealed a macroadenoma. The patient was treated with the dopamine agonist cabergoline, together with
buserelin. After 9 months of this combined treatment, the prostate-specific antigen and testosterone levels were very low;
the serum estradiol, DHEA, DHEAS, FSH and LH concentrations remained suppressed. The serum PRL level fell
dramatically to 6.95 mIU/l, and a significant reduction in tumor size was observed on MRI. In conclusion: Combined
buserelin + cabergoline treatment proved a highly successful procedure to cure this patient with prostate carcinoma
and subsequent pituitary macroprolactinoma.
Keywords: Prostate cancer, Prolactinoma, Buserelin; Cabergoline
1. Introduction
It has long been known that prostate cancer displays an
androgen sensitivity [1], and the different treatments of
prostate cancer are based on the blockade of androgen
production. This can be achieved by surgical castration
[2, 3] or by chemical or hormonal suppression of the an-
drogens. Initially, stilbestrol was administered, with
moderate success, but with significant side-effects [4];
later, treatment with the steroidal antiandrogen cyproter-
one acetate [4] or the nonsteroidal flutamide [5] was in-
In 1983, a new potent luteinizing hormone releasing
hormone analog was synthetized: [D-Ser(But)6] LHRH–
(1-9) nonapeptide ethylamide (busereline, BUS) [6,7].
Treatment with BUS greatly reduced the serum testos-
terone and prostate-specific antigen (PSA) levels [8]. The
rate of production of testosterone was lowered to values
comparable to those observed after bilateral orchidec-
tomy [10]. Chronic treatment of prostate carcinoma with
BUS, generally in patients with advanced metastatic
prostate cancer, was reported to be a safe, nontoxic and
effective form of palliation [8,9].
The prolonged administration of BUS blocks gonad-
otropin release and thereby achieves the effective sup-
pression of gonadal steroidogenesis [7]. There is no uni-
form opinion in the relevant literature as concerns the
possible changes in prolactin (PRL) secretion following
BUS treatment: unchanged or decreased [10,11] and in-
creased [12] PRL levels have all been observed. The
various changes in PRL secretion following BUS treat-
ment may be explained by differences in individual sen-
sitivity, in the doses of BUS applied, in the duration of
treatment, etc. Grotas and Nagler described the case of an
87-year-old man with prostate adenocarcinoma who had
high PRL levels and a pituitary macroadenoma [13].
The present paper reports on a case with prostate can-
cer treated with BUS, the development of prolactinoma
Combined Treatment with Buserelin + Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma
Copyright © 2010 SciRes. JCT
after 3 years of BUS administration, and the effects of
combined BUS + cabergoline (CAB) treatment.
2. Case Report
In 1997, a 63-year-old man underwent a hemicolectomy
because of colon adenocarcinoma (Grade: I. Dukes B2).
Neither regional nor systemic metastases were detected.
No X-ray or cytostatic treatment was given postopera-
tively. The patient was regularly controlled by colono-
scopy, abdominal ultrasonography, whole-body isotope
examinations and serum carcinogenic antigen (CEA)
concentration determinations. No recurrence or metasta-
sis of the colon carcinoma was observed during the sub-
sequent 12-year period. Besides the serum CEA, the se-
rum PSA level was also determined (Figure 1), which
gradually increased from the normal range (3.00 μg/ml)
in 2000 to above the critical level (10.74 μg/ml) in 2005.
The pituitary, testicular and adrenal androgen levels and
thyroid function were normal. In 2005, transrectal ultra-
sound-guided prostate needle biopsy revealed a Gleason
1 prostate adenocarcinoma (Figure 2). The immunohis-
tochemical examination confirmed the presence of the
carcinoma. The absence of the cytokeratin-5 positive
basal cell layer and a significant increase in the levels of
the p504S racemase enzyme supported the diagnosis of
carcinoma (Figure 3). Following a 4-week course of
nilutamide treatment (300 mg/d, Anandron, San-
ofi-Aventis, Paris, France), a BUS injection cure was
commenced (Suprefact Depot, Sanofi-Aventis, Paris,
France; 6.30 mg at 2-month intervals), and this treatment
was continued during the next 2 years. The PSA and tes-
tosterone levels dropped to < 0.003 μg and < 0.07 nmol/l
immediately following the initiation of BUS administra-
tion, and as side-effect impotence developed. It is note-
worthy that the patient earlier had essential hypertension
(BP: 190/110 mmHg), which was treated with antihyper-
tensive drugs (betaxolol 20 mg + indapamide 1.5 mg in
the morning and doxazosin 4 mg + amlodipin 5 mg in the
evening), and the blood pressure rapidly normalized.
However, when the combined antiandrogen treatment
was started, the blood pressure fell dramatically (80/45
mmHg) and severe hypotension developed. Accordingly,
the antihypertensive treatment was considerably moder-
ated (betaxolol 20 mg + amlodipin 5 mg/d), after which
the general circulation became stable and the antiandro-
gen treatment was continued. After 2 years of BUS
treatment, the hormonal state (Table 1) revealed that the
thyroid function (TSH, FT4, FT3) and SHBG, ACTH,
cortisol and hGH levels were normal. The serum estra-
diol, testosterone, DHEA, DHEAS, FSH and LH con-
centrations proved to be suppressed. Surprisingly, the
serum PRL concentration was extremely high (3 365
Table 1. Serum hormone levels after 2 years of buserelin
treatment (Changes: Ø: unchanged; : decreased; ↓↓:
significantly decreased; ↑↑↑: highly significantly in-
Changes Ref. range
TSH 3.19 mIU/l Ø 0.27 – 4.2
FT4 12.61 pmol/l Ø 12 – 22
FT3 4.47 pmol/l Ø 3.1 – 6.8
Estradiol < 18.4 pmol/l 28 – 156
Testosterone< 0.07 nmol/l ↓↓ 9.9 – 27.8
SHBG 33.7 nmol/l Ø 13.0 – 71.0
ACTH 3.11 pmol/l Ø 1.1 – 10.12 (8 h)
Cortisol 348 nmol/l Ø 171 – 536 (8 h)
DHEA 3.2 nmol/l 8.5 – 36
DHEAS 0.17 μmol/l 0.44 – 3.34
FSH 0.85 IU/l 1.50 – 12.40
LH 0.10 IU/l ↓↓ 1.70 – 8.60
PRL 3 365 mIU/l ↑↑↑ 86 – 324
hGH 0.34 μg/ml Ø 0.01 – 1.0
Radiologic assessment of the pituitary was performed
in the International Diagnostic Centre, Szeged, in 2009.
The MRI protocol consisted of sagittal and coronal
T1–weighted images. All scans were read by one neuro-
radiologist (EV). The MRI demonstrated a pituitary
macroadenoma measuring 0.8 cm × 1.2 cm (Figure 4(a)).
No visual field defects or neurologic symptoms were
observed. The patient was treated with CAB (2 × 0.5
mg/week) together with BUS. After 5 months of this
combined treatment, the PSA and testosterone levels
were very low; while the estradiol, DHEA, DHEAS and
FSH levels proved to be unchangingly suppressed and
the serum PRL concentration had fallen dramatically to
6.95 mIU/l, with no significant change a further 2 months
later (6.51 mIU/l). Repeated MRI demonstrated a reduc-
tion in tumor size (about 50%) (Figure 4(b)). The dose
of CAB was decreased (1 × 0.5 mg/week), and 2 months
later the serum PRL level remained very low (9.95
2000 2001 2002 20032004 2005 20062007 20082009
6.2 6. 67
10. 74
0.07 0.01 0.003 0. 003
Figure 1. The serum prostate-specific antigen (PSA) level
before and after treatme nt with buserelin.
Combined Treatment with Buserelin + Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma
Copyright © 2010 SciRes. JCT
Figure 2. Histological examination of prostatic tissue cylin-
der (hematoxilin-eosin staining).
Figure 3 . The immunohistochemical examination of prostatic
tissue cylinder.
(a) Before the cabergoline administration.
(b) After 9 months cabergoline treatment.
Figure 4 .Pituitary MR examination.
3. Discussion
Numerous data have been published on the relationship
between PRL secretion and the prostatic function in ani-
mal experiments. PRL has been stated to play a signifi-
cant role in the growth of the prostate in rodents. In con-
trast, Robertson et al. (2003) did not find any correlation
between hyperprolactinemia and prostate carcinogenesis
in PRL receptor knockout mice[14]. However, the whole
pituitary function is important in this respect: hypophy-
sectomy induced greater degree of atrophy in the rat
prostate comparable to the effect of castration [15].
Chronic treatment with the gonadotropin-releasing
analog BUS blocks gonadotropin secretion and at the
same time effectively suppresses gonadal steroidogenesis
[8]. It is somewhat surprising that the very low testoster-
one secretion during BUS treatment does not induce in-
creased FSH or LH release because of the feedback
regulation. The mode of action of this compound is not
yet fully explained.
The androgens that arise from the adrenals include the
inactive steroids androstenedione, dehydroepiandroster-
one (DHEA) and DHEA sulphate (DHEAS), which are
metabolized to testosterone and dihydrotestosterone in
the prostate itself [16]. BUS suppresses the testicular
androgens, but does not inhibit adrenal androgen produc-
tion [17]. Combined androgen blockade involving a re-
ceptor-blocking antiandrogen with BUS led to results
that were superior to those of treatment with BUS alone
In our case, the most important problem was how to
modify the treatment because of the severe hyperprolac-
tinemia. The strong argument in favor of BUS treatment
continuation is the persistence of prostate cancer. How-
ever, the introduction of specific hyperprolactinemia
treatment cannot be avoided. Supplementation of the
BUS treatment with a PRL-reducing agent was supported
when the prolactinoma was discovered by MRI as the
source of the high PRL level. The prolactinoma is the
most common subtype of active, hormone-secreting pi-
tuitary adenoma. Dopamine agonists are highly effective
in normalizing hyperprolactinemia and decreasing the
tumor size in patients with prolactinoma. CAB is a new,
potent, selective and long-acting dopamine agonist which
blocks PRL secretion. Reports on long-term CAB treat-
ment, indicated that it was better tolerated [18] than bro-
mocriptine and side-effects seldom developed. Delgrange
et al. (2009) [19] described the normalization of high
PRL levels in (96% of their cases) and significant tumor
shrinkage (in 82%) during CAB administration to 122
patients with macroprolactinoma. In our case, the starting
dose of CAB was 0.5 mg twice weekly, and after treat-
ment for 5 months the serum PRL concentration had
Combined Treatment with Buserelin + Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma
Copyright © 2010 SciRes. JCT
fallen to 6.95 mIU/l and significant tumor shrinkage was
observed on MRI. Finally, the dose of CAB was reduced
to 0.5 mg/week.
As an unpleasant side-effect, severe hypotension, de-
veloped immediately after the introduction of antiandro-
gen therapy. We earlier observed that androgens are able
to increase the sensitivity of blood vessels to vasocon-
striction induced by different vasoactive agents (e.g.
vasopressin), and antiandrogen compounds (cyproterone
acetate or flutamide) can prevent this effect of androgens
[20]. Hypotension induced by antiandrogen administra-
tion is not a well-known side-effect, and attention should
be drawn to this important aspect. At the beginning of
antiandrogen therapy, we have to control the blood pres-
sure frequently, and if necessary to reduce the doses of
antihypertensive drugs.
In conclusion: The combined treatment with BUS +
CAB proved to be a highly successful procedure in this
patient with prostate adenocarcinoma and pituitary
macroprolactinoma. The minimal length of CAB treat-
ment recommended by The Pituitary Society is 1-3 years
[1] C. Huggins and C. V. Hodges, “Studies on Prostatic
Cancer. I. The Effect of Castration on Serum Phosphata-
ses in Metastatic Carcinoma of the Prostate,” Cancer Re-
search, Vol. 1, No. 1941, pp. 293-296.
[2] C. E. Blackard, D. P. Byar and W. P. Jordan, Jr., Or-
chidectomy for Advanced Prostatic Carcinoma. A Re-
evaluation, Urology, Vol. 1, No. 6, 1973, pp. 553-560.
[3] F. Sciarra, G. Sorcini, F. Di Silverio and V. Gagliardi,
Plasma Testosterone and Androstenedione after Or-
chiectomy in Prostatic Adenocarcinoma, Clinical Endo-
crinology (Oxford), Vol. 2, No. 2, 1973, pp. 101-109.
[4] H. J. de Voogt, P. H. Smith, M. Pavone-Macaluso, M. de
Pauw and S. Suciu, Cardiovascular Side Effects of Di-
ethylstilbestrol, Cyproterone Acetate, Medroxypro-
gesterone Acetate and Estramustine Phosphate Used for
the Treatment of Advanced Prostatic Cancer: Results
from European Organization for Research on Treatment
of Cancer Trials 30761 and 30762, The Journal of Urol-
ogy, Vol. 135, No. 2, 1986, pp. 303-307.
[5] R. A. Airhart, T. F. Barnett, J. W. Sullivan, R. L. Levine
and J. U. Schlegel, “Flutamide Therapy for Carcinoma of
the Prostate,” Southern Medical Journal, Vol. 71, No. 7,
1978, pp. 798-801.
[6] G. Tolis, N. Faure, M. Koutsilieris, A. Lemay, S. Klioze,
A. Yakabow and A. T. Fazekas, Suppression of Testicu-
lar Steroidogenesis by the GnRH Agonistic Analogue
Buserelin (HOE-766) in Patients with Prostatic Cancer:
Studies in Relation to Dose and Route of Administra-
tion,” Journal of Steroid Biochemistry, Vol. 19, No. 1C,
1983, pp. 995-998.
[7] J. Trachtenberg, The Treatment of Metastatic Prostatic
Cancer with a Potent Luteinizing Hormone Releasing
Hormone Analogue,The Journal of Urology, Vol. 129,
No. 6, 1983, pp. 1149-1152.
[8] G. Mathe, A. V. Schally, A. M. Comaru-Schally, R. Y.
Mauvernay, M. L. Vovan, D. Machover, J. L. Misset, B.
Court, P. Bouchard, J. Duchier and et al., Phase II Trial
with D-Trp-6-LH-RH in Prostatic Carcinoma: Compari-
son with Other Hormonal Agents, The Prostate, Vol. 9,
No. 4, 1986, pp. 327-342.
[9] H. J. de Voogt, U. Studer, F. H. Schroder, J. G. Klijn, M.
de Pauw and R. Sylvester, Maximum Androgen Block-
ade Using LHRH Agonist Buserelin in Combination with
Short-term (two weeks) or Long-term (continuous)
Cyproterone Acetate is Not Superior to Standard Andro-
gen Deprivation in the Treatment of Advanced Prostate
Cancer. Final Analysis of EORTC GU Group Trial 30843.
European Organization for Research and Treatment of
Cancer (EROTC) Genito-Urinary Tract Cancer Coopera-
tive Group, European Urology, Vol. 33, No. 2, 1998, pp.
[10] H. Parmar, R. H. Phillips, S. L. Lightman, L. Edwards, L.
Allen and A. V. Schally, Randomised Controlled Study
of Orchidectomy vs Long-acting D-Trp-6-LHRH Micro-
capsules in Advanced Prostatic Carcinoma, Lancet, Vol.
2, No. 8466, 1985, pp. 1201-1205.
[11] J. Waxman, Gonadotrophin Releasing Hormone Ana-
logues for Prostatic Cancer: An Overview, Seminars in
Oncology, Vol. 15, No. 4, 1988, pp. 366-370.
[12] H. Matzkin, I. Kaver, O. Lewyshon, D. Ayalon and Z.
Braf, The Role of Increased Prolactin Levels under Gnrh
Analogue Treatment in Advanced Prostatic Carcinoma,
Cancer, Vol. 61, No. 11, 1988, pp. 2187-2191.
[13] A. B. Grotas and H. M. Nagler, Presentation of a Func-
tional Pituitary Adenoma as a Significant Decrease in
Prostate-Specific Antigen Level in a Patient Followed for
Prostate Cancer, The Canadian Journal of Urology, Vol.
13, No. 6, 2006, pp. 3346-3347.
[14] F. G. Robertson, J. Harris, M. J. Naylor, S. R. Oakes, J.
Kindblom, K. Dillner, H. Wennbo, J. Tornell, P. A. Kelly,
J. Green and C. J. Ormandy, “Prostate Development and
Carcinogenesis in Prolactin Receptor Knockout Mice,
Endocrinology, Vol. 144, No. 7, 2003, pp. 3196-3205.
[15] A. Peyre, J. P. Ravault and P. Laporte, Potentiation Ef-
fect of Endogenous Prolactin on Male Sex Effectors
Treated with Testosterone, Comptes rendus des séances
de la Société de biologie et de ses filiales, Vol. 162, No. 8,
1968, pp. 1592-1595.
[16] F. Labrie, A. Belanger, V. Luu-The, C. Labrie, J. Simard, L.
Cusan, J. Gomez and B. Candas, Gonadotpin-releasing
Hormone Agonists in the Treatment of Prostate Cancer,
Endocrine Reviews, Vol. 26, No. 3, 2005, pp. 361-379.
[17] I. M. Spitz, B. Chertin, A. Fridmans, A. Farkas, A.
Belanger, H. Hartman and F. Labrie, Partial Androgen
Suppression Consequent to Increased Secretion of Adre-
Combined Treatment with Buserelin + Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma
Copyright © 2010 SciRes. JCT
nal Androgens in a Patient with Prostate Cancer Treated
with Long-acting GnRH Agonists, Prostate Cancer and
Prostatic Diseases, Vol. 12, No. 1, 2009, pp. 100-103.
[18] E. Ciccarelli, M. Giusti, C. Miola, F. Potenzoni, D.
Sghedoni, F. Camanni and G. Giordano, Effectiveness
and Tolerability of Long Term Treatment with Cabergo-
line, a New Long-lasting Ergoline Derivative, in Hyper-
prolactinemic Patients, The Journal of Clinical Endo-
crinology and Metabolism, Vol. 69, No. 4, 1989, pp.
[19] E. Delgrange, T. Daems, J. Verhelst, R. Abs and D.
Maiter, Characterization of Resistance to the Prolac-
tin-lowering Effects of Cabergoline in Macroprolactino-
mas: A Study in 122 Patients, The European Journal of
Endocrinology, Vol. 160, No. 5, 2009, pp. 747-752.
[20] F. A. Laszlo, C. Varga, A. Papp, I. Pavo and F. Fahren-
holz, Difference between Male and Female Rats in
Vasopressor Response to Arginine Vasopressin, Acta
Physiologica Hungarica, Vol. 81, No. 2, 1993, pp.
[21] F. F. Casanueva, M. E. Molitch, J. A. Schlechte, R. Abs,
V. Bonert, M. D. Bronstein, T. Brue, P. Cappabianca, A.
Colao, R. Fahlbusch, H. Fideleff, M. Hadani, P. Kelly, D.
Kleinberg, E. Laws, J. Marek, M. Scanlon, L. G. So-
brinho, J. A. Wass and A. Giustina, Guidelines of the
Pituitary Society for the Diagnosis and Management of
Prolactinomas, Clinical Endocrinology (Oxford), Vol.
65, No. 2, 2006, pp. 265-273.