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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 significant 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 cabergoline 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 anemia 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 anemia. Clinicians should be watchful for this rare side effect induced by cabergoline.
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DOI 10.1515/jpem-2013-0151J 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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160Gürbüz etal.: 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 2months 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. Twoweeks
previously, cabergoline treatment had been started at
0.5mg/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 was127.8 (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 (90–180mg/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 1MRI 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 (2.5mg once per
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Gürbüz etal.: Cabergoline-induced immune hemolytic anemia161
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 1Laboratory 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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162Gürbüz etal.: 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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... As a consequence of a wide array of pharmacological actions at multiple receptors, dopamine agonists such as bromocriptine and cabergoline have multiple side effects that could broadly be classified into three major categories: (1) side effects related to the gastrointestinal system (most commonly, nausea, vomiting, abdominal pain and constipation), (2) side effects related to the cardiovascular system (including that of fibrosis of cardiac valves) and (3) side effects related to the neurological system (most commonly, headaches, drowsiness, dizziness and weakness). [10][11][12] An important side effect to note is that of psychosis which occurs less frequently, and is fully reversible with the cessation of usage of dopamine agonists. 12 Other psychiatric side effects such as anxiety and depression occur more commonly, yet are not easily picked up clinically. ...
... [10][11][12] An important side effect to note is that of psychosis which occurs less frequently, and is fully reversible with the cessation of usage of dopamine agonists. 12 Other psychiatric side effects such as anxiety and depression occur more commonly, yet are not easily picked up clinically. 12 Side effects are dose related, and patients who are susceptible usually present at the initial stages of medical treatment with dopamine agonists. ...
... 12 Other psychiatric side effects such as anxiety and depression occur more commonly, yet are not easily picked up clinically. 12 Side effects are dose related, and patients who are susceptible usually present at the initial stages of medical treatment with dopamine agonists. 11 12 Approximately 9 months after the onset of medical treatment, the patient developed significant tricuspid valve regurgitation which was moderately severe on 2D-echocardiogram. ...
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Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.
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According to the World Health Organization classification of pituitary tumors, only tumors with systemic metastasis must be considered as carcinomas. Invasive tumors with multiple recurrences are only classified as aggressive tumors or "atypical adenomas". To illustrate the problems encountered in the pathological diagnosis of pituitary carcinoma and in patient management, we present two male patients operated on for an aggressive prolactin pituitary adenoma with and without metastasis. In case 1, 5 surgeries, 3 irradiations, increased doses of dopamine agonists, and trials of temozolomide and carboplatine-VP16 failed to control tumor progression and the appearance of metastases which lead to death 16 years after onset. In case 2, based on the initial diagnosis of an aggressive-invasive adenoma that was resistant to dopamine agonists, gamma-Knife irradiation was initially performed on the intra-cavernous remnant. Eight years after onset, the remnant remained stabilized and the plasma PRL normalized under dopamine agonist. From these 2 cases alongside other cases found in the literature, we propose that the association of certain clinical signs (male sex, dopamine-resistant hyperprolactinemia), radiological signs (invasive macro or giant tumor on MRI) and histological signs (angiogenesis, Ki-67 > 3 %, p53 positive, mitoses >2 per high power field, vascular invasion, up-regulation of genes related to invasion and proliferation, and allelic loss of chromosome 11) might suggest aggressiveness and be suspicious of malignancy before the appearance of metastasis. The early detection of an aggressive phenotype of a prolactin pituitary tumor should permit the earlier establishment of the optimum therapeutic strategy associating surgery and radiotherapy to delay or inhibit metastasis.
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Dopamine agonist administration is the primary therapy for macroprolactinomas, but bromocriptine is the only agent approved in the United States. Its use is limited by a high incidence of side effects, a short duration of action, and a lack of effectiveness in some patients. Cabergoline is a long-acting dopamine agonist specific for the D2 receptor that is more effective and better tolerated than bromocriptine in women with microadenomas or idiopathic hyperprolactinemia. However, experience with cabergoline in the treatment of patients with macroadenomas is limited. We report the first study of chronic administration of cabergoline conducted exclusively in patients with macroprolactinomas. Fifteen patients (8 women, 7 men) ages 18-76 yr were studied in an open-label 48-week dose escalation trial of cabergoline administered once per week. Eleven patients had received prior therapy with other dopamine agonists. Mean prolactin (PRL) levels decreased by 93.6%, and normal levels were attained in 73% of patients at doses of 0.5-3.0 mg per week. Three of five patients who had failed to normalize PRL on prior dopamine agonists achieved normal levels. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea. Tumor size decreased in 11 of the 15 patients. Side effects were minimal. Of the 5 patients who had experienced side effects in prior dopamine agonists, 4 had none on cabergoline, and the fifth had milder symptoms. During two further years of follow up, the improvement in PRL levels, gonadal function, and tumor size has persisted during cabergoline administration, and three patients have experienced a further decline in PRL and/or tumor size. This study demonstrates the effectiveness and minimal side effects of once-weekly cabergoline for treatment of macroprolactinomas.
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