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DOI 10.1515/jpem-2013-0151J Pediatr Endocr Met 2014; 27(1-2): 159–163
Patient report
Fatih Gürbüz, Begül Yağcı-Küpeli, Yılmaz Kör, Bilgin Yüksel, Suzan Zorludemir, Berrak
Bilginer Gürbüz and Serhan Küpeli*
The first report of cabergoline-induced immune
hemolytic anemia in an adolescent with
prolactinoma
Abstract: Prolactinomas are common pituitary tumors that
can cause gonadal dysfunction and infertility related to
hyperprolactinemia. Dopamine agonists are the first-line
treatment in these patients. Cabergoline leads to signifi-
cant reduction in serum prolactin levels and tumor size in
patients with prolactinoma. Dopamine agonists have been
associated with adverse effects such as nausea, vomiting
and psychosis. We report here a case with cabergoline-
induced immune hemolytic anemia. The patient had caber-
goline treatment history for prolactinoma and presented
with weakness, fatigue, nausea, and paleness. Laboratory
findings revealed severe anemia-related immune hemolysis.
There were no causes identified to explain hemolytic ane-
mia except cabergoline. Therefore, cabergoline therapy was
stopped and subsequently hemolytic anemia resolved and
did not occur again. This is the first reported pediatric case
with prolactinoma and cabergoline-induced hemolytic ane-
mia. Clinicians should be watchful for this rare side effect
induced by cabergoline.
Keywords: cabergoline; hemolytic anemia; prolactinoma.
*Corresponding author: Serhan Küpeli, MD, MSc, Çukurova University
Faculty of Medicine, Department of Pediatric Oncology, 01330,
Adana, Turkey, Phone: +905357634549, Fax: +903223387444,
E-mail: serkupeli@yahoo.com
Fatih Gürbüz and Bilgin Yüksel: Çukurova University Faculty of
Medicine, Department of Pediatric Endocrinology, 01330, Adana,
Turkey
Suzan Zorludemir: Çukurova University Faculty of Medicine,
Department of Pathology, 01330, Adana, Turkey
Begül Yağcı-Küpeli: Numune Training Hospital, Department of
Pediatric Oncology, 01330, Adana, Turkey
Yılmaz Kör: Numune Training Hospital, Department of Pediatric
Endocrinology, 01330, Adana, Turkey
Berrak Bilginer Gürbüz: Numune Training Hospital, Department of
Pediatrics, 01330, Adana, Turkey
Introduction
Prolactinoma is characterized by hypersecretion of prolac-
tin which is derived from lactotroph cells in the pituitary
gland (1). They are the most frequent pituitary adenomas,
and account for approximately 40% of all pituitary adeno-
mas, with an estimated prevalence of 60–100 per million
(2). Prolactinoma cause sexual and gonadal dysfunction
related to hyperprolactinemia, and symptoms associated
with tumor expansion. Hyperprolactinemia causes hypo-
gonadotropic hypogonadism in both men and women
because of the inhibitory effect of increased prolactin
concentrations on hypothalamic gonadotropin releasing
hormone release. The diagnosis of hyperprolactinemia
can be easily made in women of reproductive age because
it presents with oligo/amenorrhoea and infertility. In con-
trast, symptoms are more subtle and even nonexistent
in men, except when the tumor causes signs of pituitary
gland enlargement such as headache and visual field
defects (3).
Prolactinomas are classified according to their diam-
eter as microprolactinomas ( < 10 mm), macroprolac-
tinomas ( ≥ 10 mm), and giant prolactinomas ( > 40 mm)
(3). In patients with macroprolactinomas, hypopituita-
rism, other than hypogonadism, is present in 45% of the
patients (4–7). Suprasellar extension of the adenoma
often compresses the optic chiasm and classically results
in bitemporal hemianopia and diminished visual acuity.
Visual field defects are approximately present in 35% of
the patients with macroprolactinomas (4–6). Medical
therapy with dopamine agonists is the initial treatment
of prolactinoma. The most commonly used dopamine
agonists are the ergot-derived dopamine agonists bro-
mocriptine and cabergoline, and the non-ergot-derived
dopamine agonist quinagolide. These drugs inhibit pro-
lactin secretion and reduce tumor size (8, 9). Dopamine
agonists have a wide spectrum of pharmacological actions
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160Gürbüz etal.: Cabergoline-induced immune hemolytic anemia
at different receptors (10). Therefore, these drugs display a
number of side effects. Several studies have demonstrated
the efficacy of cabergoline in normalizing prolactin con-
centrations, and in inducing tumor shrinkage, especially
in microprolactinomas. Cabergoline-induced much fewer
and less severe side effects than other dopamine agonists,
as only 4% of the patients had to discontinue treatment
(9, 11).
Herein, we report the first adolescent patient with
severe immune hemolytic anemia associated with caber-
goline treatment for prolactinoma.
Case
A 16-year-old female with a history of transsphenoidal
surgery performed 2months previously because of atypi-
cal pituitary adenoma applied with weakness fatigue,
nausea, and paleness that have been present for 2 weeks.
Additionally, she had had a headache and loss of vision for
2 months, since the diagnosis of prolactinoma. Twoweeks
previously, cabergoline treatment had been started at
0.5mg/twice a week for high prolactin levels (470 ng/mL).
She felt weakness, fatigue, nausea, and paleness after
initiation of cabergoline.
The physical examination findings were normal
except for significant paleness. Laboratory findings
revealed severe anemia (Hgb 4.7g/dL; hematocrit 11.4;
WBC 10.4.106/μL; MCV 86.2 fL; MCH 35.6 pg; and reticu-
locyte 4%) with direct coombs (+++) and no electrolyte
imbalance. The patient’s hormonal profile included FT4
0.81 (0.60–1.2 ng/dL); TSH 1.6 (0.27–4.2 mIU/L); FSH 1.54
IU/L; LH 0.54 IU/L. Serum prolactin was127.8 (86–324
ng/mL). Growth hormone was 0.231 ng/mL. TORCH,
EBV, parvovirus B19-Ig M, hepatitis markers, Salmo-
nella and Brucella agglutination were negative. Com-
plement C3: 151.7 mg/dL (90–180mg/dL); complement
C4: 45.1 mg/dL (10–40 mg/dL). Brain and the pituitary
magnetic resonance imaging (MRI) showed a 24-mm
residual pituitary tumor with evidence of postoperative
changes (Figure 1). The specimens of the patient were
fixed overnight in 10% buffered formalin. The tissues
were processed routinely, cut into 5 μm thick sections
and stained with hematoxylin and eosin (H-E), reticu-
lin and PAS histochemical stains. Immunohistochemi-
cal (IHC) staining for anterior pituitary hormones was
performed using the strept-avidin-biotin peroxidase
complex method. Antisera used in IHC studies included
ACTH (monoclonal, 1:150, Novocastra, Newcastle,
UK), GH (polyclonal, 1:200, Zymed, San Francisco, CA,
Figure 1MRI image before surgery.
USA), [alpha]- subunit (monoclonal, 1:400, Biogenex,
San Ramon, CA, USA), FSH (monoclonal, 1:50, Dako,
Denmark Carpinteria, CA, USA), TSH (monoclonal, 1:50,
Dako, Denmark Carpinteria, CA, USA), Prolactin (poly-
clonal, 1:200, Dako, Denmark Carpinteria, CA, USA),
and CAM 5.2 (monoclonal, prediluted; Becton Dickin-
son, NJ, USA), MIB-1 (rabbit monoclonal, prediluted,
Ventana, Tucson, AZ, USA), p53 protein (monoclonal,
1:200, Dako, Denmark Carpinteria, CA, USA). Micro-
scopy revealed a pituitary adenoma. The adenoma cells
manifested paranuclear immunoreactivity for prolactin.
Immunostaining for other pituitary hormone types and
CAM 5.2 were negative. MIB-1 labeling index was 7%. p53
was nuclear positive in 25%–30% of tumor cells. Based
on these immunohistochemical findings, a diagnosis
of atypical prolactin cell adenoma (prolactinoma) was
confirmed (Figure 2A–D).
Bone marrow aspiration findings were normal except
for erythroid hyperplasia. The patient’s complete blood
count values were normal before the treatment with
cabergoline (Table 1). The erythrocyte suspension was
transfused to the patient for severe anemia and cardiac
insufficiency symptoms. Patient’s hemolytic anemia con-
tinued despite transfusion. The cabergoline therapy was
stopped because no causes were identified to explain
hemolytic anemia except drugs.
At week 4 of cabergoline cessation, the second opera-
tion was performed on the patient for residual pituitary
tumor while her complete blood count values were normal
without any findings regarding hemolytic anemia. Control
brain and the pituitary MRI after the second operation
showed no residual pituitary tumor. However, her serum
prolactin levels were still higher than normal values
(202.2 ng/mL). Bromo criptine treatment (2.5mg once per
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Gürbüz etal.: Cabergoline-induced immune hemolytic anemia161
AB
CD
Figure 2(A) Nucleolar prominence and increased mitotic activity. H-E × 400. (B) The paranuclear positive immunoreactivity for prolactin.
Prolactin × 400. (C) Positive nuclear p53 immunoreactivity in tumor cells. P53 protein × 400. (D) Showing increased proliferative activity.
MIB-1 × 400.
Table 1Laboratory values before and after cabergoline.
Hemoglobin, g/dL Hematocrit, % Prolactin, ng/mL ACTH, pg/mL GH, ng/mL
Before the operation (with no cabergoline) . . . .
First week after the operation (with no
cabergoline)
. .
Second week after the operation (with no
cabergoline)
Third week after the operation (with no
cabergoline)
. .
Fist week after cabergoline treatment . . .
Second week after cabergoline treatment
(on admission)
. . . .
After erythrocyte suspension transfusion
and stopped cabergoline treatment
. . > . .
Third week after stopped cabergoline
treatment (before second operation)
. .
Fourth week after cabergoline treatment
is stopped
. . . .
Fifth week after cabergoline treatment is
stopped
. . . .
day) was started for elevated prolactin levels. Increases
in prolactin values were controlled with bromocriptine in
approximately 2 months. The patient’s hemolytic anemia
did not recur again.
Discussion
Prolactinomas are the most common functioning pituitary
adenomas and respond well to medical treatment (12, 13).
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162Gürbüz etal.: Cabergoline-induced immune hemolytic anemia
Dopamine agonists are used in treatment of prolactinoma
(14). Surgery is indicated for patients who are non-respon-
sive or intolerant to dopamine agonists, as well as in
patients with invasive macroadenomas and compromised
vision whose clinical condition does not rapidly improve
after medical treatment. Success rates of transsphenoidal
surgery differ between micro and macroprolactinomas.
Furthermore, surgical success rates are highly depend-
ent upon the experience of the neurosurgeon (15). In our
patient the surgery was chosen at the first step because
the patient had symptoms of compression. Subsequently
however, cabergoline treatment was started because of
residual pituitary tumor with high serum prolactin levels.
Although the dopamine agonist bromocriptine has
been widely used in patients with prolactinoma, the
recently developed dopamine agonist cabergoline is a
longer-acting and more selective agent for dopamine type
2 (D2)-receptor. Additionally, cabergoline is more effective
and better tolerated than bromocriptine for normalizing
prolactin levels and shrinking tumors in patients (16).
Side effects of these drugs can be grouped into three
categories; gastrointestinal, cardiovascular, and neuro-
logical. Symptoms tend to occur after the first dose and
after increases of the dose, but can be minimized by
introducing the drug in a low dose at bedtime. Nausea
and vomiting are the most common gastrointestinal side
effects. Headache and drowsiness are the most frequent
neurological adverse effects. Psychiatric adverse effects,
such as psychosis, are infrequent and entirely reversible
when the drug is discontinued (17). Anxiety and depres-
sion occur frequently during treatment with dopamine
agonists. But these psychological side effects are often
subtle and therefore difficult to detect. The dopamine
agonists pergolide, bromocriptine, and cabergoline have
been associated with increased risk of cardiac valve regur-
gitation in patients with Parkinson’s disease and retro-
peritoneal and pulmonary fibrosis (18–29).
Drug-induced immune hemolytic anemia (DIIHA)
is an uncommon cytopenia; more than 130 drugs have
been incriminated. The antibodies causing DIIHA can be
drug dependent (antibodies react in vitro with red blood
cells (RBCs) only in the presence of the drug, on the RBC
membrane or when added to the patient’s plasma and
RBCs) or drug independent [the drug is not required to be
present to detect antibodies in vitro and DIIHA antibody
presents clinically and serologically as an autoimmune
hemolytic anemia (AIHA) with red cell (RBC) autoanti-
bodies] (30).
Our patient had severe immune hemolytic anemia.
The erythrocyte suspension was transfused to the patient
for severe anemia. After the cessation of cabergoline
therapy, no hemoglobin and/or hematocrit decrease was
observed in consecutive controls of complete blood count
values. In our patient, no cause was identified to explain
hemolytic anemia, except cabergoline. Her clinical condi-
tion may be explained as DIIHA, because her hemolytic
anemia stopped after the cessation of cabergoline therapy.
In the literature, cabergoline-induced immune hemolytic
anemia has been rarely reported (31). To date (Novem-
ber 2012), 1391 people had been reported to have side
effects when taking cabergoline. Among them, two people
(0.14%) had hemolytic anemia, but there was no child or
adolescent among the cases.
Radiotherapy has a limited role in the treatment of
prolactinomas. In most cases, it is chosen after unsuccess-
ful transsphenoidal surgery or, after medical therapy alone
and in cases with atypical adenomas (32). Usually it is
reflected as a third-line therapy after the failure of medical
and surgical treatments (3). Although radiotherapy is used
in atypical pituitary adenomas, radiotherapy was not
given in our patient and it will be considered if there is a
recuurrence or elevation of serum prolactin levels.
In conclusion, we report the first pediatric patient
with cabergoline-induced severe immune hemolytic
anemia. Although the cabergoline is more effective and
better tolerated than other dopamine agonists, this life-
threatening rare side effect should be taken into account
while using this agent in medical treatment of prolactino-
mas in children and adolescents. Routine complete blood
count monitoring may be useful in order to detect such
abnormalities.
Received April 16, 2013; accepted July 16, 2013; previously published
online August 14, 2013
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