Open Journal of Urology, 2012, 2, 153-156
http://dx.doi.org/10.4236/oju.2012.223029 Published Online October 2012 (http://www.SciRP.org/journal/oju)
Changes in Electrocardiogram Findings during Treatment
with Gonadotropin-Releasing Hormone Agonist and
Surgical Castration for Prostate Carcinoma
Hasan Sağlam1, Akif Çakar2, Osman Köse3, Şükrü Kumsar3, Salih Budak3,
Serbülent Gökhan Beyaz4*, Öztuğ Adsan1
1Department of Urology, Sakarya University Medical School, Sakarya, Republic of Turkey
2Department of Cardiology, Sakarya University Training and Research Hospital, Sakarya, Republic of Turkey
3Department of Urology, Sakarya University Training and Research Hospital, Sakarya, Republic of Turkey
4Anesthesiology and Pain Management Center, Sakarya University Medical School, Sakarya, Republic of Turkey
Received July 4, 2012; revised August 6, 2012; accepted September 10, 2012
ABSTRACT
Purpose: To investigate electrocardiogram (ECG) changes after complete androgen blockade (CAB) achieved by either
surgical or medical castration and compare the outcomes of the groups. Methods: Sixty-three consecutive men (be-
tween 58 - 86 years of age) requiring CAB for prostate cancer were enrolled in the study. Patients with diabetes mellitus,
an additional malignancy, coronary heart disease, atrial fibrillation, heart failure or a medical history of cardiac event in
the last 12 months were excluded from the study. Additionally, those who were taking medicine affecting heart rate
were excluded. The participants were divided into two groups according to their modality of castration. The first group
consisted of 35 patients who received bilateral orchiectomy plus anti-androgen medication. The second group contained
28 patients who accepted gonadotropin-releasing hormone (GnRH) plus anti-androgen therapy. After complete exami-
nations and biochemical tests, the ECG leads of the patients were obtained conveniently. This was then repeated at
three- and six-month visits. ECG findings (including heart rate, PR, QRS, QT, corrected QT (QTc) intervals and QT
dispersion (QTd)) were recorded and analysed statistically. The groups were then compared in terms of pre- and
post-treatment ECG outcomes. Results: Both groups revealed similarly lower heart rate and prolonged PR, QRS, QT,
corrected QTc and QTd by the end of six months. By the end of three months, all variables had changed significantly in
the orchiectomy group, whereas in the GnRH group, they had not. Conclusion: CAB may result in lower heart rate and
prolonged QT, a condition associated with fatal cardiac arrhythmia and sudden death. Therefore, patients receiving
CAB should be monitored closely for cardiac adverse effects.
Keywords: Gonadotropin-Releasing Hormone; Castration; Testosterone; Electrocardiogram; QT Interval; Heart Rate
1. Introduction
Prostate cancer has been shown to be the second most
common malignancy and sixth leading cause of death in
men worldwide. Epidemiological studies reveal that its
incidence is on the rise in the era of prostate-specific
antigen (PSA) [1,2]. In contrast to localised prostate
cancer for which many therapeutic modalities exist (in-
cluding radiotherapy, surgery, chemotherapy etc.), in
metastatic prostate cancer, hormonal therapy (i.e. andro-
gen deprivation therapy (ADT)) is the treatment of
choice as an initial therapy. ADT is achieved by either
surgical removal of the bilateral testes or medical therapy
with gonadotropin releasing-hormone (GnRH) analogues
or antagonists. It has traditionally been a cornerstone in
the treatment of advanced or metastatic prostate cancer,
and it has been effectively used for two to three years on
average [3]. If such a deprivation therapy is used in con-
junction with an androgen receptor antagonist to block
the effects of androgens of adrenal origin, it is termed a
combined androgen blockade (CAB) [4].
Hormonal therapy is also being used for localised
prostate cancer in high-risk patients. Therefore, the use
of ADT in the earlier and later stages of prostate cancer
has increased over time, and consequently, more men are
being treated with ADT for longer periods [5]. Cardio-
vascular disease (CVD) has recently been investigated as
one of the adverse effects of ADT, which may be due to
interference with the cardioprotective effect of testoste-
rone. Despite male gender is a risk factor for CVD, data
*Corresponding author.
C
opyright © 2012 SciRes. OJU

H. SAĞLAM ET AL. 154
are increasing on cardioprotection of testosteron. ADT
has been shown to increase approximately 10% of adipo-
sity and cholesterol increase which are risk factors for
CVD. Hypogonadism has been found to be associated
with hyperinsulinemia which may elevate cardiac risk
through a link to diabetes. Lower serum testosterone has
also been associated with a prothrombotic state, which
may predispose men to myocardial infarction. Studies of
animal models of atherosclerosis have demonstrated that
after castration, aortic atherosclerosis was increased
[4,6,7].
In this study, in addition to above mentioned effects of
ADT on the heart, we have aimed to investigate the ef-
fects of CAB on ECG measures that might be suggestive
of cardiac adverse effects and compare the results of the
group received GnRH plus anti-androgen therapy with
those of the group received bilateral orchiectomy plus
anti-androgen therapy.
2. Materials and Methods
Between May 2010 and January 2012, a total of 63 con-
secutive patients who received CAB, aged between 58
and 86 years (mean 76 ± 8), were enrolled in this study.
Patients with diabetes mellitus, an additional malignancy,
coronary heart disease, atrial fibrillation, heart failure or
a medical history of cardiac event in the last 12 months
were excluded from the study. Additionally, those who
were taking medicine affecting heart rate (e.g. calcium
channel blockers, beta-blockers or statins) were excluded.
Before castration, complete routine biochemical tests,
hormone analyses and ECGs were obtained. The patients
were assigned to one of two groups: 1) patients who re-
ceived bilateral orchiectomy + anti-androgen therapy
(bicalutamide 50 mg, 1 × 1) or 2) patients who received
GnRH analogue + anti-androgen therapy (bicalutamide
50 mg, 1 × 1). Orchiectomies of the 31 patients were
carried out concomitantly with transurethral resection of
the prostate (TURP), and four other patients underwent
an orchiectomy only. In the 31 patients, orchiectomies
and TURP were carried out under spinal anaesthesia with
2 cc of 1% prilocaine solution. The other four patients
underwent orchiectomy under local anaesthesia with 1%
prilocaine solution. Thirty-five patients in the orchiec-
tomy group were started on oral anti-androgen therapy
just after the operation. The other group of patients was
given anti-androgen therapy one week before the GnRH
started (goserelin 10.8 mg, sc, n = 8; leuprolide acetate
11.25 mg, sc, n = 10; and leuprolide acetate 22.5 mg, sc,
n = 9). Three and six months after initiation of CAB, the
patients were re-examined, and the previous analyses
were performed again. ECGs were analysed with respect
to heart rate, PR, QRS, QT, QTc intervals and QTd by
the same cardiologist. The results were recorded and
evaluated statistically. The data of the pre- and post-
treatment conditions were compared within groups and
between groups using the paired t-test and the student’s
t-test, respectively, with a p-value of <0.05 being consid-
ered significant.
3. Results
Before the treatment, the two groups were similar with
respect to all variables, including age and ECG deriva-
tion interval outcomes (p > 0.05) (Table 1).
Three months later, heart rate decreased from the pre-
treatment value of 75 ± 10 beats per minute (b/m) to 72 ±
6 b/m (p = 0.017) and from 76 ± 8 b/m to 68 ± 5 b/m (p =
0.001) in the medical and surgical castration groups, re-
spectively. Pre-treatment QTc changed from 412 ± 27 ms
to 422 ± 40 ms (p = 0.49) and 422 ± 29 ms to 440 ± 34
ms (p = 0.007) in the medical and surgical groups, re-
spectively. In the same period, QTd increased from 29 ±
6 ms to 33 ± 7 ms (p = 0.001) in the medical group and
from 29 ± 6 ms to 41 ± 8 ms (p = 0.001) in the surgical
group. Findings at the end of three and six months and
comparisons between the groups are presented in Table
2.
Table 1. Pretreatment characteristics of the patients.
Surgical group Medical group
BO + antiandrogen GnRH + antiandrogenp
n 35 28 -
Age (years)77 ± 8 74 ± 8 NS
RR (b/m) 76 ± 8 75 ± 10 NS
Qtc (ms) 422 ± 29 412 ± 27 NS
BO: bilateral orchiectomy, n: number of the patients, NS: nonsignificant,
b/m: beats per minute, ms: milisecond.
Table 2. ECG interval values three and six months after
initiation of CAB.
3 months later 6 months later
Interval Medical
treatment
Surgical
treatment p Medical treatment
Surgical
treatment p
RR (b/m)72 ± 668 ± 5 0.011 67 ± 6 65 ± 5 NS
PR (ms)174 ± 14175 ± 15NS 178 ± 11 180 ± 11NS
QRS (ms)94 ± 1496 ± 14 NS 104 ± 15 100 ± 15NS
QT (ms)394 ± 29398 ± 32NS 415 ± 19 414 ± 34NS
QTc (ms)422 ± 40440 ± 330.055 434 ± 41 448 ± 34NS
QTd (ms)33 ± 741 ± 8 0.001 43 ± 8 46 ± 8 NS
b/m: beats per minute, NS: not significant: p > 0.05.

H. SAĞLAM ET AL. 155
4. Discussion
In this study, we have demonstrated that cardiac conse-
quences of CAB reflected by ECG were markedly evi-
dent six months after the onset of therapy for all patients.
As with heart rate, all variables detectable on ECG were
changed significantly. QT and QTc increased after CAB,
but as has been stated by Yang, it was a major challenge
to specifically determine the association between sex
steroid hormones and arrhythmia susceptibility, since the
cardiac system is highly complex. The specific effect
ought to be studied in isolation (i.e. without other con-
tributing factors) [8].
Among the androgens, testosterone in particular is
widely believed to be associated with a higher risk of
CVD in men [9]. This is primarily suggested to be due to
androgen abuse, which has been associated with fatal
consequences, including myocardial infarction, hyper-
tension, arrhythmia, cardiac failure and sudden death [10,
11]. The effect of testosterone on CVD in men has never
been investigated in a clinical, double-blind, placebo-
controlled study. In contrast, it is proposed that natural
androgens in general have a preventive effect in men
with regard to CVD, similar to that of oestrogens in
women [12].
Conflicting experimental and clinical data exist re-
garding the effects of sex steroids, especially testosterone
and oestrogen, on the hearts of both genders. In animal
models, the physiological levels of androgens have been
stated to be positively related with parasympathetic ac-
tivity. In contrast, decreased androgen levels in aging
males have been stated to have controversial effects on
autonomic function. Regarding the autonomic control of
the heart, adrenal androgens have been proposed as being
crucial. However, data differs according to a number of
factors, including subject type (i.e. human or animal),
gender, hormones studied, hormone dose, duration of
exposition, concomitant pathology etc. [9,13,14].
Although being male is a risk factor for coronary art-
ery disease, increasing evidence suggests that testoster-
one may actually have a cardioprotective effect in men
[7]. Experimental animal studies also provide evidence
that testosterone has a cardioprotective effect [15,16].
Keating et al. reported that men receiving ADT had a
25% higher risk of incident coronary artery disease than
eugonadal men [17]. It has been assumed that ADT
strongly inhibits not only the hormonal modulation of
prostate cancer cells but also that of the cardiac ventricu-
lar myocytes. It has been suggested that this therapy af-
fects ventricular repolarisation, including increasing QT
intervals [18] and ventricular arrhythmias [19].
The autonomic system has been proposed to be in-
volved in human sex hormone status. Physiologic testos-
terone and dehydroepiandrosterone sulphate levels have
been found to be positively associated with parasympa-
thetic and negatively correlated with sympathetic activi-
ties. Serum oestradiol levels have also been stated to be
negatively correlated with parasympathetic and posi-
tively correlated with sympathetic activities [13]. Al-
though the findings of our study seem contrary to this
explanation, the patients we studied were beyond the
physiological status after CAB. Other studies also seem
to report opposite findings [20,21], but regarding the
abovementioned studies, they did not exactly conduct
their work by denoting heart rate variability in men with
CAB. We have shown that heart rate decreased markedly
after CAB achieved medically or surgically.
Although statistical analyses showed great similarities
between the groups by the end of three months in terms
of PR, QRS and QT, values of the surgical group were
significantly different in terms of RR, QTc and QTd in-
tervals. These earlier significant changes in the surgical
group may have been due to an acute onset of a fall in
testosterone and oestradiol. By the end of six months,
both groups revealed significantly lowered heart rate and
increased PR, QRS, QT, QTc and QTd measures.
Noord et al. concluded that lower QTc intervals in
men were associated with higher male sex hormones [22].
In accordance with this study, in our patients, CAB was
shown to be related with longer QT and QTc intervals.
On the other hand, others have stated that the temporal
effects of low testosterone levels were related with shor-
ter QT intervals in men with primary and secondary hy-
pogonadism as well as in experimental animal obser-
vations following orchiectomy [23,24].
Being a retrospective study and having a small number
of patients may be first prominent limitations of this
study with respect to reaching an exact conclusion. Ano-
ther issue may be that the medical castration group was
heterogeneous due to the fact that three similar but dif-
ferent medications were administered. Additionally, in-
formation about daily physical activity changes, smoking
and other factors comprising metabolic syndrome was
not collected completely. A general challenge that should
obviously also be addressed is the difficulty in calculat-
ing QT intervals accurately.
In conclusion, CAB, with either medical or surgical
castration of men with prostate cancer, results in similar
ECG changes six months after the initiation of therapy.
Surgical castration reveals outcomes earlier than medical
castration in terms of heart rate, QTC and QTd. ECG
changes suggest that castration may result in increased
QTc, a condition associated with ventricular tachycardia,
a fatal cardiac adverse event. Therefore, patients receiv-
ing hormone therapy such as CAB for prostate cancer
should be followed up regarding cardiac consequences.
Further large-scale and prospective studies may shed
light on the adverse cardiac effects of the castration of
patients with prostate cancer.

H. SAĞLAM ET AL. 156
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