Changes in Electrocardiogram Findings during Treatment with Gonadotropin-Releasing Hormone Agonist and Surgical Castration for Prostate Carcinoma

doi:10.4236/oju.2012.223029

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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

Email: *[email protected]

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.

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

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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