Frequent Episodic Vertigo is an Unexpected Side Effect of Flutamide

doi:10.4236/pp.2011.24043

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Pharmacology & Pharmacy, 2011, 2, 338-340

doi:10.4236/pp.2011.24043 Published Online October 2011 (http://www.SciRP.org/journal/pp)

Frequent Episodic Vertigo Is an Unexpected Side

Effect of Flutamide

Jiann-Jy Chen1,2, Dem-Lion Chen3*

1Department of Medical Imaging, Taipei Medical University & Shuang Ho Hospital, New Taipei, Chinese Taipei; 2Department of

Otorhinolaryngology, Tao-Yuan Hospital, Department of Health, Executive Yuan, Taoyuan, Chinese Taipei; 3G-Home Otorhi-

nolaryngologic Clinic, Kaohsiung, Chinese Taipei.

Email: *[email protected]

Received April 28th, 2011; revised May 28th, 2011; accepted July 29th, 2011.

ABSTRACT

An 82-year-old male suffered from prostatic cancer five years ago. Since then, he has taken flutamide and was bothered

with episodic vertigo (EV) every morning. In order to treat prostatic cancer, flutamide was not discontinued, but con-

servative treatment and life-style change were recommended. Finally, EV actually subsided. Herein, we report the rare

case, in which EV was an unexpected side effect of flutamide. Herein we review his whole history, physical examination,

vestibular function test, electronystagmogram, caloric test, awake encephalogram, blood examinations, color-coded

duplex ultrasonogram and magnetic resonance imaging/angiogram to suggest a mechanism of flutamide responsible for

EV.

Keywords: Flutamide, Episodic Vertigo, Prostatic Cancer

1. Introduction

Flutamide (4’-nitro-3’-trifluoromethylisobutyranilide) could

antagonize the nuclear androgen receptors of prostatic

cancer, and inhibits intake of androgen; so, it has been

widely applied to treat prostatic cancer. The main ad-

verse reactions are reported diarrhea, nausea, vomiting,

gastrointestinal distress, gynecomastia, muscular cramps

and cardiovascular complications [1,2], and never epi-

sodic vertigo in the literature, but we encountered a case

of frequent episodic vertigo after taking flutamide. Here-

in we report it because of rare curiosity and suggest a m-

chanism responsible for the side effect.

2. Case Report

A right-handed 82-year-old male has height 166 cm,

weight 55 kg, and body mass index 20.0 kg/m2. He did

not suffer head trauma, hypertension, diabetes mellitus,

heart disease, migraine or psychosis; neither did he have

any hobby of cigarette smoking, alcohol drinking, areca

chewing, or coffee consumption. However, he has regu-

larly taken doxazosin (Doxaben) or terazosin (Hytrin) to

treat benign prostatic hyperplasia for 12 years. Five years

ago, he unfortunately got stage II prostatic adenocarci-

noma and began taking anti-androgen flutamide (Fugerel)

every day. Since then, he has bothered with episodic ver-

tigo every early morning. Changing position exacerbated

symptom, and only bed rest would relieve symptom in

half an hour. There was no headache, blurred vision,

ataxia, syncope, tinnitus, hearing block or other neurolo-

gic signs.

Three years ago, he first visited our emergency due to

sever episodic vertigo with nausea and vomiting. Blood

pressure (heart rate) was 122/78 mmHg (59/min). One

hour after he was treated conservatively, symptoms sub-

sided, and blood pressure (heart rate) was 142/89 mmHg

(86/min). Then, Doxazosin or Terazosin was discontin-

ued, but episodic vertigo still recurred every early morn-

ing. Last July, he visited our emergency again. Blood

pressure (heart rate) was 128/79 mmHg (47/min). When

symptoms subsided, blood pressure (heart rate) rose to

138/89 mmHg (72/min). Computed tomography of brain

was unremarkable. In the following three days, he was

assigned to the author for a battery of studies.

Physical examination and vestibular function test were

normal, except that squat to stand test or hyperventilation

test provoked the same vertigo. Electronystagmogram,

caloric test, awake encephalogram and blood examina-

tions were unremarkable. Color-coded duplex ultrasono-

gram (EnVisor, Philips, USA) revealed mild atheroscle-

rosis over bilateral common carotid arteries, and total

Frequent Episodic Vertigo Is an Unexpected Side Effect of Flutamide339

cerebral flow volume was 760 mL/min, which was the

sum of bilateral internal carotid arterial volumes and bi-

lateral vertebral arterial volumes (Table 1). Twenty-four

hours’ Holter showed that heart rate was averaged 68

beats/min with highest 114 beats/min (8:00 am) and low-

est 42 beats/min (4:00 AM). T1, T2, fluid-attenuated

inversion recovery and diffusion weighted image mag-

netic resonance imaging (1.5 Tesla system, Picker Edge

Eclipse, Picker 98 International, USA) did not find any

lesion, but time of flight magnetic resonance angiogram

(TOF MRA)(TR/TE/excitation: 29/6/1) showed central

vascular anomalies: 1) posterior incomplete circle of

Willis (Figure 1(a)) and 2) tortuous vertebrobasilar ar-

tery (Figure 1(b)).

In order to suppress prostatic cancer, flutamide was

not discontinued, so he was conservatively treated with

diphenidol (Cephadol), ginkgo flavone (Jinbo), and aspi-

rin (Bokey); besides, he was asked to slow down getting

up or changing position in early morning. One week later,

symptom did not recur any more. In the following half a

year, it was uneventful although he did not take dipheni-

dol, ginkgo flavone, and aspirin any more.

3. Discussion

He has been bothered with episodic vertigo every early

morning for five years. Doxazosin or terazosin, long-

acting selective α1-antagonist, is known to treat benign

prostatic hyperplasia and hypertension by relaxing

smooth muscle of vessels, urinary bladder and prostate;

however, it could induce dizziness (vertigo), fatigue,

hypotension, edema and dyspnea via the same mecha-

nism [3,4]. α1-antagonists have been discontinued after

1st-time emergency, but symptom did not relieve any

more; thus, symptom was by far not a side effect of

α1-antagonist. Symptom always subsided after heart rate

and blood pressure have risen in these two emergencies;

besides, squat to stand test and hyperventilation test in-

duced the same symptom; thus, symptom was associated

with cardiovascular dysfunction and central nervous he-

modynamic instability although 24-hour electrocardio-

gram was normal.

Seventy four point six percent of 18 - 89 year-old Tai-

wanese have defects of posterior circle of Willis, and

among them, 57.4% are short of bilateral posterior com-

municating arteries (Figure 1(a)) [5], and communica-

tion of anterior and posterior circulation must be limited

[6]. It is probable that vertebrobasilar arterial system de-

generated abnormally in the 5th embryologic week, and

resulted in bilateral intracranial vertebral artery tortuosity.

After birth, asymmetric blood flows of vertebral artery

gradually bended basilar artery year by year (Figure 1(b))

[7]. Finally, tortuous vertebrobasilar artery might become

locally more thrombogenic secondary to vascular resis-

Table 1. Color-coded duplex ultrasonogram of extracranial

vertebral arteries.

Diameter

(mm)

Average velocity

(cm/sec)

Average flow

(ml/min)

Resistance

index

Right3.09 14.9 67 0.69

Left3.68 16.3 104 0.65

(a) (b)

Figure 1. (a) TOF MRA showed dislinkage of anterior and

posterior circulation (dotted lines) due to absence of bilat-

eral posterior communicating arteries; (b) the axis of ver-

tebrobasilar artery (black line) rotated clockwise (dou-

ble-headed curved arrow). The upper extreme and middle

of basilar artery (diameter 4.0 mm) were respectively 2.9

mm (hollow arrow head) and 5.1 mm (hollow arrow) apart

from mid-line (white spotted line). Before connecting basi-

lar artery, right vertebral artery (diameter 2.0 mm) formed

a sigmoid route, and so did left vertebral artery (diameter

3.8 mm) a crooked route. The rightward extreme of left

vertebral artery was 4.5 mm (filled arrow) apart from mid-

line (white spotted line), and approximated to right verte-

bral artery (filled arrow head).

tance. Therefore, these central vascular anomalies might

incur vertebrobasilar artery insufficiency at specific con-

dition although neck duplex scanning was unremarkable

(Table 1).

Androgen is known to not only keep artery or arteriole

sensitive to baroreflex [8], but also provoke the pathway

of nitrogen-monoxide genesis in central nervous system,

activating angiotensin II system and raising blood pres-

sure [9]. After he has had to regularly take Flutamide to

suppress prostatic cancer, Flutamide has antagonized

androgen receptors of central nervous system, heart, and

peripheral arterioles; so, regulation of blood pressure and

heart rate were limited.

Sudden getting up or changing position could incur

transient vertebrobasilar artery insufficiency secondary to

postural hypotension, especially during low sympathetic

tone in early morning. We suggest that not only age, but

also Flutamide has limited the immediate compensation

Frequent Episodic Vertigo Is an Unexpected Side Effect of Flutamide

340

of heart rate and blood pressure for transient vertebro-

basilar artery insufficiency; fortunately, simply episodic

vertigo resulted, but not ischemia stroke. However, it was

beyond neck duplex scanning to identify transient verte-

brobasilar insufficiency; besides, it was beyond electro-

nystagmogram and caloric test to identify transient ves-

tibulopathy.

In order to suppress prostatic cancer, Flutamide was

not discontinued, and conservative treatment and life-style

change were recommended as below. Diphenidol has

been tried to relieve vertigo. Ginkgo flavone and aspirin

have also been tried to decrease the vascular resistance of

vertebrobasilar artery. In order to spare his heart enough

time to compensate for postural hypotension, he was

asked to slow down getting up or changing position. As a

result, episodic vertigo did not recur in one week despite

daily flutamide. In the following over half a year, it was

uneventful although he has not taken diphenidol, ginkgo

flavone and aspirin any more. Herein, we report the case,

in which EV was an unexpected side effect of flutamide.

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