Heart rate variability of young men with idiopathic hypogonadotropic hypogonadism

Heart rate variability of young men with idiopathic hypogonadotropic hypogonadism

Autonomic Neuroscience: Basic and Clinical 152 (2010) 84–87 Contents lists available at ScienceDirect Autonomic Neuroscience: Basic and Clinical j o...

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Autonomic Neuroscience: Basic and Clinical 152 (2010) 84–87

Contents lists available at ScienceDirect

Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

Heart rate variability of young men with idiopathic hypogonadotropic hypogonadism Necip Ermis a,⁎, Ferhat Deniz b, Alper Kepez c, Batuhan Kara d, Omer Azal b, Mustafa Kutlu b a

Baskent University, Adana Teaching and Medical Research Center, Cardiology Department, 01250 Yuregir, Adana, Turkey Gulhane Military Medical Academy, Department of Endocrinology and Metabolism, Ankara, Turkey c Etimesgut Military Hospital, Department of Cardiology, Ankara, Turkey d Etimesgut Military Hospital, Department of Radiology, Ankara, Turkey b

a r t i c l e

i n f o

Article history: Received 17 May 2009 Received in revised form 17 July 2009 Accepted 31 August 2009 Keywords: Hypogonadotropic hypogonadism Cardiac autonomic modulation Heart rate variability

a b s t r a c t Background: There is little data available regarding the effects of male sex hormones on cardiac autonomic function. The aim of this study is to evaluate the association between hormones of male hypothalamo–pitiutary– gonadal axis and cardiac autonomic function by comparing heart rate variability (HRV) parameters of young male idiopathic hypogonadotropic hypogonadism patients with those of healthy controls. Methods: The study consisted of 22 male idiopathic hypogonadotropic hypogonadism patients (mean age 20.8± 1.2 years) and the same number of age-matched healthy male controls (mean age 21.0± 1.5 years). A 24-hour Holter monitoring was performed to assess the time and frequency-domain parameters. The HRV parameters of patients and control groups were compared, and possible associations between levels of tested hormones and HRV parameters were evaluated. Results: The standard deviation of all NN intervals (SDNN), standard deviation of the averages of NN intervals in all 5 min segments (SDANN), power in low frequency range (LF, ms²) and power in high frequency range (HF, ms²) values of patients were significantly lower compared to those of controls (147.47 ± 56.16 vs. 193.63± 40.89; 138.31± 57.64 vs. 190.15± 43.94; 397.8 ± 236.7 vs. 491.5 ± 208.4; and 133.6± 97.4 vs. 198.5 ± 91.6 respectively; p < 0.05 for all). Significant negative correlations were observed between serum FSH, LH and testosterone levels and most of the HRV parameters. Conclusions: Deficiency in the male hypothalamo–pituitary–gonadal axis seems to adversely affect cardiac autonomic modulation with increased sympathetic and decreased parasympathetic components of HRV. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Gender is known to have a profound influence on the risk of cardiovascular diseases. Epidemiological studies have demonstrated that premenopausal women suffer much less from ischemic heart disease (Kalin and Zumoff, 1990; Liu et al., 2003a,b). The risk of death from ischemic heart disease in women lags 10 years behind men. However, the gap in incidence rates narrows with advancing age (Lerner and Kannel, 1986). Gender- related differences have been attributed to estrogens due to the anti-atherosclerotic effects of this hormone as shown in several animal studies (Adams et al., 1990; Wagner et al., 1991; Kaplan et al., 2002). Additionally, there is accumulating evidence that estrogen reduces cellular hypertrophy, enhances vessel wall elasticity, and has anti-oxidative and anti-inflammatory properties (Adams et al., 1990; Wagner et al., 1991; Kaplan et al., 2002; Paoletti et al., 1997). The influence of male sex hormones other than estrogen on cardiovascular pathophysiology has however received much less attention (Liu et al., 2003a,b).

⁎ Corresponding author. Tel.: +90 322 3272727x2094; fax: +90 322 3271274. E-mail address: [email protected] (N. Ermis). 1566-0702/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2009.08.018

There is controversy regarding the influence of testosterone on atherosclerosis progression and coronary artery disease risk factors. Experimental and clinical studies demonstrate that there is a significant relationship between autonomic nervous system and cardiovascular mortality, including sudden death. Heart rate variability (HRV) is a statistical measure of the cyclic beat-to-beat variation, and has been shown to be a useful non-invasive tool for assessing the cardiac autonomic function. Diminished HRV is associated with increased sympathetic and decreased vagal modulation, and these autonomic changes have been associated with higher cardiovascular risk. Patients with reduced HRV after a myocardial infarction has been shown to have increased mortality and HRV is accepted as an accurate predictor of mortality after myocardial infarction (Reed et al., 2005). More recently, work has concentrated on attempts to predict the timing of onset of fatal ventricular tachyarrhythmias. However, while the prognostic value of HRV after myocardial infarction is well established evidence of value in ventricular tachyarrhythmias and sudden death is less clear (Reed et al., 2005). Several physiological and pathological conditions may alter HRV (Marek, 1996). Previous studies observed that sex-related differences in HRV and both androgens and estrogens have been suggested to have an influence on autonomic nervous system function, and thus on HRV

N. Ermis et al. / Autonomic Neuroscience: Basic and Clinical 152 (2010) 84–87

(Huikuri et al., 1996; Hinojosa-Laborde et al., 1999; Liu et al., 2003a,b; Wranicz et al., 2004). In this study, our purpose is to evaluate the influence of male hypothalamo–pitiutary–gonadal axis on cardiac autonomic modulation by comparing HRV parameters of young men with idiopathic hypogonadotropic hypogonadism to those of healthy controls. We also aim to investigate the possible associations between tested hormones and HRV parameters. 2. Materials and methods 2.1. Subjects The study group consisted of 22 young male idiopathic hypogonadotropic hypogonadism patients (age 20.8 ± 1.2 years) who were referred to military hospital for their evaluation regarding eligibility for military service. Also, twenty-two, age-matched, and healthy male subjects constituted our control group. All subjects underwent clinical, metabolic, radiologic and hormonal assessments. Patients with a history of any kind of cardiac disease, arterial hypertension, diabetes mellitus, smoking habitus, any kind of metabolic or psychiatric disease and medication of any kind were excluded from study. Other exclusion criteria were the presence of any kind of pituitary tumor or any other hypothalamic–pituitary diseases. Patients with other hormone deficiencies were also excluded due to possible confounding effects. Hypogonadism was defined by symptoms of androgen deficiency and total morning serum testosterone levels less than 300 ng/dL. All subjects gave written informed consent, and the study protocol was approved by the Institutional Ethical Committee. 2.2. Analysis of hormonal parameters Venous blood samples were collected from an antecubital vein, between 08:00 and 09:00 a.m., after an overnight fast. The samples were analysed for luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), prolactin (PRL), estradiol (E2), progesterone (PROG), thyrotropin (thyroid-stimulating hormone = TSH), free triiodothyronine (FT3), free tetraiodothyronine (L-thyroxine= FT4). The detection limit of testosterone was 7 ng/dL. The minimal detectable concentrations (MDC) of FSH and LH were estimated to be 1.0 and 0.2 mIU/ml, respectively. Assay sensitivity of E2 was 10 pg/ml. Serum levels of all hormones were assessed by immunoenzymometric assay method (TOSOH-II ST AIA-PACK TOSOH Bioscience Incorporation, San Francisco, California 94080, USA). 2.3. Analysis of heart rate variability parameters A 24-hour Holter monitoring was performed to all subjects. Recordings were obtained using 3-channel analog recorders, and analysed by a blinded observer using the ELATEC Holter system (ELA Medical). All the cases were told not to make any extraordinary changes in the normal course of their daily life. This was confirmed during the removal of the device from the subjects. The time and frequency-domain analysis of HRV were performed according to the recommendation of the European Society of Cardiology task force (Marek, 1996). The mean heart rate, standard deviation of all NN intervals (SDNN), standard deviation of the averages of NN intervals in all 5 min segments of the entire recording (SDANN), root mean square of successive differences (RMSSD), and HRV triangular index (TRIA) were measured in the time domain analysis of HRV. While SDNN and HRV triangular index reflect overall HRV, SDANN reflect HRV's long-term components, and RMSSD reflect its short-term components. A reduced SDNN has been considered to reflect a diminished autonomic modulation of sinus node. The power spectrum of HRV was measured using fast-Fourier transform analysis in three frequency bands: <0.04 Hz (very low frequency, VLF), 0.04– 0.15 Hz (low frequency, LF) and 0.15–0.4 Hz (high frequency, HF). HF


was used as a marker of the parasympathetic nervous system and LF was used as a marker of sympathetic and parasympathetic activity. The power of these components was stated as ms². We also measured the ratio of low- high frequency power (LF/HF) reflecting the sympatho– vagal balance. 2.4. Statistical analysis Statistical analysis was performed using the SPSS for WINDOWS (version 11.0; SPSS Inc., Chicago, Illinois, USA). Ordinal parameters displaying normal distribution were expressed as mean± SD and ordinal parameters not displaying normal distribution were expressed as median (interquartile range). Differences between groups were tested by Student t tests for unpaired data once normality was demonstrated. Otherwise, a nonparametric test (Mann–Whitney) was used. Correlations between variables were performed by the Pearson (normally distributed) and Spearman rank correlation test. A p value less than 0.05 was considered significant. 3. Results Baseline demographic features, lipid and hormonal profiles are presented in Table 1. There were no significant differences between groups regarding age, BMI and lipid parameters. However, all sex hormones were significantly lower in patients group compared to controls. In terms of the 24-hour time and frequency-domain HRV parameters; SDNN, SDANN, LF (ms²) and HF (ms2) values of patients were significantly lower and LF/HF ratio was higher compared to those of the control groups (Table 2). Bivariate correlation analysis demonstrated significant positive correlation between FSH, LH, testosterone levels and most of time domain HRV parameters (Table 3). There was no significant correlation between estradiol or progesterone levels and any HRV parameters. 4. Discussion The main finding of this study is that both time and frequencydomain HRV parameters are significantly lower in hypogonadotropic hypogonadism patients compared with controls. So it may be safe to suggest that hypogonadism patients display tonic autonomic imbalance as a result of decreased parasympathetic activity. Both serum gonadotropin and testosterone levels were found to be significantly correlated with HRV parameters. As our subjects consisted of young men without any known condition that may have a potential to alter the HRV parameters, our results suggest the influence of hypothalamic–pituitary– gonadal axis on cardiac autonomic modulation in a population of young men.

Table 1 Baseline characteristics of patient and control groups.

Age (years) BMI (kg/m2) Cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglyceride (mg/dL) FSH (mIU/ml) LH (mIU/ml) Testosterone (ng/dL) Estradiol (pg/ml) Progesterone (ng/ml) Prolactin (ng/ml) TSH (mIU/ml)

Patients (n = 22)

Controls (n = 22)

p value

20.8 ± 1.2 22.26 ± 1.32 175.62 ± 31.25 104.85 ± 25.91 48.33 ± 11.87 104.61 ± 48.51 2.30 ± 1.11 1.38 ± 0.77 49.78 ± 17.37 19.0 (5.0) 0.42 (0.12) 5.35 ± 1.64 1.49 ± 0.40

21.0 ± 1.5 23.02 ± 1.14 165.94 ± 24.46 94.20 ± 20.62 48.05 ± 7.00 104.83 ± 48.93 5.11 ± 1.55 3.27 ± 1.40 513.69 ± 95.34 28.0 (10.20) 0.56 (0.16) 6.52 ± 2.42 1.60 ± 0.65

0.609 0.732 0.129 0.181 0.932 0.989 0.004 0.001 < 0.001 0.028 0.023 0.196 0.611

Abbreviations: BMI, body mass index; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.


N. Ermis et al. / Autonomic Neuroscience: Basic and Clinical 152 (2010) 84–87

Table 2 Twenty-four hour time and frequency-domain HRV parameters of patient and control groups.

Mean heart rate (/min) SDNN (msec) SDANN (msec) TRIA RMSSD (msec) HF (ms² /Hz) LF (ms²/Hz) LF/HF

Patients (n = 22)

Controls (n = 22)

p value

79.4 ± 12.5 147.47 ± 56.16 138.31 ± 57.64 595.84 ± 170.30 57.05 ± 31.28 133.6 ± 97.4 397.8 ± 236.7 3.17 ± 1.5

76.7 ± 14.1 193.63 ± 40.89 190.15 ± 43.94 586.83 ± 214.19 65.26 ± 19.00 198.5 ± 91.6 491.5 ± 208.4 2.66 ± 1.3

0.78 0.006 0.004 0.88 0.33 0.009 0.028 0.03

Abbreviations: SDNN, standard deviation of all NN intervals; SDANN, standard deviation of the averages of NN intervals in all 5 min segments; RMSSD, root mean square of successive differences; TRIA, HRV triangular index; LF, the power spectrum of low frequency band (0.04–0.15 Hz) and HF, the power spectrum of high frequency band (0.15–0.4 Hz ).

Although previous studies did demonstrate sex-related differences, there is still little data available regarding the effects of male sex hormones on heart rate variability. The existing data are mainly based on studies related to the postmenopausal hormone replacement therapy, or those evaluating autonomic nervous system functions in different phases of menstrual cycle (Yildirir et al., 2001; Gokce et al., 2005; Farag et al., 2002; Leicht et al., 2003). The data from those studies emphasize the favorable effect of estrogen on HRV and that progesterone partly attenuates this favorable profile. Apart from estrogens, even much less is known regarding the effects of androgens on HRV parameters. In an HRV study on young women with polycystic ovary syndrome, Yildirir et al. found increased sympathetic and decreased parasympathetic tone. According to the authors, altered hormonal profile (lower plasma estradiol and higher plasma testosterone levels in patients with polycystic ovary syndrome) is responsible for the unfavourable HRV parameters (Yildirir et al., 2006). In another study, Wranicz et al. evaluated time domain HRV parameters of men with history of myocardial infarction, and found significant positive correlation between HRV measures of parasympathetic activity and testosterone levels. The correlation continued to remain significant after adjustment for age, ejection fraction, and other relevant clinical covariates. There was no significant association between estradiol and HRV parameters (Wranicz et al., 2004). In an experimental animal study, ElMas et al. demonstrated the favorable role of testosterone on baroreceptor control of reflex bradycardia by enhancing cardiomotor vagal activity (El-Mas et al., 2001). How male sex hormones may affect cardiac autonomic modulation is not clear. Based on the observed correlation between serum gonadotropin levels and HRV parameters, it may be suggested that central nervous system may be involved in this relationship. Testosteronespecific androgen receptors are described in the primates' brain (Sheridan, 1983). In a recent report, exogenous testosterone administration was found to attenuate the central stress response in healthy Table 3 Correlation analysis between HRV parameters and sex hormones.





r = 0.405 p = 0.012 r = 0.430 p = 0.007 r = 0.202 p = 0.224 r = 0.277 p = 0.093 r = 0.361 p = 0.024 r = 0.4 p = 0.013 r = 0.354 p = 0.026

r = 0.439 p = 0.006 r = 0.440 p = 0.006 r = 0.098 p = 0.558 r = 0.336 p = 0.039 r = 0.424 p = 0.008 r = 0.373 p = 0.035 r = 0.395 p = 0.015

r = 0.393 p = 0.015 r = 0.375 p = 0.02 r = 0.187 p = 0.260 r = 0.292 p = 0.075 r = 0.385 p = 0.02 r = 0.412 p = 0.009 r = 0.383 p = 0.017

young women (Hermans et al., 2007).Authors suggested that the attenuating effect of testosterone may be partly due to its effect on central regions such as amygdala, brainstem, and other hypothalamic nuclei, which are involved in the endocrine and autonomic response mechanisms to stress. Testosterone-dependent promotion of parasympathetic dominance may also come from its positive effect on coronary blood flow. Coronary vasodilator effect of testosterone has been shown in men with coronary artery disease (Webb et al., 1999). There are also some suggestions that heart rate changes may be partly controlled by cardiovascular androgen receptors. Bricout et al. described androgen receptors in the rabbit heart (Bricout et al., 1994). Hartman et al. detailed the influence of testosterone application on sympathetic activity of intracardiac nerves in mice (Hartmann et al., 1986). In conclusion, our results suggest that hypogonadotropic hypogonadism has an unfavourable effect on cardiac autonomic modulation with sympathetic dominance, and that activity of hypothalamic– pituitary–gonadal axis is associated with more favorable profile. Our findings support the Barrett–Connor hypothesis that isosexual hormone deficiency may be harmful for the cardiovascular system (BarrettConnor, 1996). 5. Study limitations Small sample size is the main limitation of this study that limits the generalization of our findings. Small sample size of our study also precluded construction of multivariate analysis model due to strong correlations between serum FSH, LH and testosterone levels themselves. Also our study was a cross-sectional study performed on a population of young male patients who were referred for their evaluation regarding eligibility for military service. Further studies with larger populations are needed to define the mechanism by which male sex hormones affect the cardiac autonomic modulation and to observe whether male sex hormone replacement by physiological means reverses the effects of hormone deficiency in those patients. Acknowledgements The authors wish to thank Dr. Erdal Kokcan, and Dr. Dilek Abasli for performing the biochemical measurements. References Adams, M.R., Kaplan, J.R., Manuck, S.B., Koritnik, D.R., Parks, J.S., Wolfe, M.S., Clarkson, T.B., 1990. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone. Atherosclerosis 10, 1051–1057. Barrett-Connor, E., 1996. Testosterone, HDL-cholesterol and cardiovascular disease, In: Bhasin, S., Gabelnick, H.L., Spieler, J.M., Swerdloff, R.S., Wang, C., Kelly, C. (Eds.), Pharmacology, biology, and clinical applications of androgens: current status and future prospects, 2nd edn. Wiley-Liss, New York, pp. 215–223. Bricout, V.A., Germain, P.S., Serrurier, B.D., Guezzennec, C.Y., 1994. Changes in testosterone muscle receptors. Effects of an androgen treatment on physically trained rats. Cell. Mol. Biol. (Noisy-le-grand) 40, 291–294. El-Mas, M.M., Afify, E.A., Mohy El-Din, M.M., Omar, A.G., Sharabi, F.M., 2001. Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components. J. Cardiovasc. Pharmacol. 38, 754–763. Farag, N.H., Nelesen, R.A., Parry, B.L., Loredo, J.S., Dimsdale, J.E., Mills, P.J., 2002. Autonomic and cardiovascular function in postmenopausal women: the effects of estrogen versus combination therapy. Am. J. Obstet. Gynecol. 186, 954–961. Gokce, M., Karahan, B., Yilmaz, R., Orem, C., Erdol, C., Ozdemir, S., 2005. Long term effects of hormone replacement therapy on heart rate variability, QT interval, QT dispersion and frequencies of arrhytmia. Int. J. Cardiol. 99, 373–379. Hartmann, G., Addicks, K., Donike, M., Schanzer, W., 1986. Testosterone application influences sympathetic activity of intracardiac nerves in non-trained and trained mice. J. Auton. Nerv. Syst. 17, 85–100. Hermans, E.J., Putman, P., Baas, J.M., Gecks, N.M., Kenemans, J.L., Van Honk, J., 2007. Exogenous testosterone attenuates the integrated central stress response in healthy young women. Psychoneuroendocrinology 32, 1052–1061. Hinojosa-Laborde, C., Chapa, I., Lange, D., Haywood, J.R., 1999. Gender differences in sympathetic nervous system regulation. Clin. Exp. Pharmacol. Physiol. 26, 122–126. Huikuri, H.V., Pikkujamsa, S.M., Airaksinen, K.E., Ikaheimo, M.J., Rantala, A.O., Kauma, H., Lilja, M., Kesaniemi, Y.A., 1996. Sex-related differences in autonomic modulation of heart rate in middle-aged subjects. Circulation 94, 122–125.

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