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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 1881-1885
Copyright © 1998 by The Endocrine Society

Original Studies

Intense Sympathetic Nerve Activity in Adults with Hypopituitarism and Untreated Growth Hormone Deficiency1

Yrsa Bergmann Sverrisdóttir, Mikael Elam, Hans Herlitz, Bengt-Åke Bengtsson and Gudmundur Johannsson

Institute for Clinical Neuroscience, Department of Clinical Neurophysiology (Y.B.S., M.E.), Department of Nephrology (H.H.), and Research Center for Endocrinology and Metabolism (G.J., B.-Å.B.), Sahlgren University Hospital, S-413 45 Goteborg, Sweden

Address all correspondence and requests for reprints to: Dr. Yrsa Bergmann Sverrisdóttir, Institute for Clinical Neuroscience, Department of Clinical Neurophysiology, Sahlgren University Hospital, S-413 45 Goteborg, Sweden. E-mail: yrsa.sverrisdottir{at}neuro.gu.se


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Perturbations in the sympathetic nervous system may be anticipated in adults with hypopituitarism and untreated GH deficiency, because the syndrome is associated with both peripheral and central factors known to modulate sympathetic traffic. The higher prevalence of hypertension and increased cardiovascular morbidity/mortality reported in GH-deficient patients may suggest increased activity of the sympathetic nervous system.

We recorded muscle sympathetic nerve activity (MSNA) in 10 hypopituitary adults with adequate hormonal replacement therapy except GH and in 10 healthy controls matched for age, gender, and body mass index to test whether hormonal aberrations in hypopituitarism and untreated GH deficiency are associated with an increase in sympathetic nerve traffic.

Blood samples for insulin-like growth factor I, free T4, and TSH were taken after an overnight fast, followed by an oral glucose tolerance test. Direct intraneural recordings of MSNA were performed with a tungsten microelectrode from the peroneal nerve.

The hypopituitary subjects had markedly increased MSNA (54 ± 4 bursts/min vs. 34 ± 4 in controls; P < 0.002), which was not related to abdominal obesity or altered glucose metabolism. When assessed for the whole study group, MSNA was inversely correlated to serum insulin-like growth factor I (r = -0.59; P < 0.006) and TSH (r = -0.46; P < 0.04). MSNA was positively correlated to diastolic blood pressure (r = 0.80; P < 0.0005) in patients, but not in controls.

The intense sympathetic discharge is suggested to be of central origin and may be an important underlying mechanism for the secondary hypertension and increased cardiovascular morbidity/mortality in this patient group.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADULTS with hypopituitarism and untreated GH deficiency have a higher prevalence of hypertension (1) and increased cardiovascular morbidity/mortality (2) compared to the normal population. GH deficiency in adults is associated with both peripheral and central factors known to modulate sympathetic nerve traffic. Abnormal body composition with excessive adiposity, abdominal/visceral obesity (3), and insulin resistance (4) are common features of the syndrome, known to affect the autonomic nervous system (5, 6). Furthermore, central hypothalamic releasing factors, such as corticotropin-releasing factor (CRF) and TRH, are known to modulate sympathetic outflow (7, 8), but the effects of GH/insulin-like growth factor I (IGF-I) aberration on sympathetic activity are not known. However, the higher prevalence of hypertension (1), lower glomerular filtration rate (9), reduced aortic distensibility (10), and increased cardiovascular morbidity/mortality (2) reported in GH-deficient patients may suggest an increase in sympathetic nerve traffic.

Although the relationship between sympathetic nerve activity and hypertension remains controversial (11, 12, 13, 14, 15), the fact that hyperactivity of the sympathetic nervous system constitutes an important risk factor for cardiovascular mortality (16, 17) is well established. A putative sympatho-excitation in patients with hypopituitarism may, together with abdominal obesity, dyslipoproteinemia, and insulin resistance, underlie the pronounced increase in vascular morbidity/mortality in this patient group (2, 18).

The aim of the present study was to evaluate the effect of hormonal aberrations in hypopituitary adults on resting muscle sympathetic nerve activity (MSNA). To minimize the impact of peripheral sympatho-modulating factors known to be associated with hypopituitarism, the patients were compared to a healthy control group matched for body mass index (BMI), which resulted in a lack of significant group differences in metabolic and body composition variables. The results indicate that hypopituitarism is associated with a centrally elicited robust sympatho-excitation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study groups consisted of 10 patients with known pituitary deficiency and 10 healthy control subjects matched for age, gender, and body mass index (see Table 2Go). GH deficiency was verified by an insulin tolerance test with a peak GH response of less than 3 µg/L at a blood glucose nadir of less than 2.2 mmol/L. When appropriate, all patients had received stable replacement therapy with glucocorticoids, T4, gonadal steroids, and desmopressin at least 6 months before study start (Table 1Go). Two patients with prolactinoma received treatment with bromocriptine. The study was approved by the ethics committee at the University of Goteborg, and all subjects gave informed consent.


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  		Table 2. Characteristics of 10 hypopituitary patients and 10 healthy controls matched in terms of age, gender, and BMI

 

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  		Table 1. Cause of hypopituitarism in 10 patients and their hormonal replacement therapies

 
Study design

This was a cross-sectional case-control study. All subjects where studied in the morning after an overnight fast. Body weight was measured to the nearest 0.1 kg, and body height was measured barefoot to the nearest 0.01 m. BMI was calculated as body weight in kilograms divided by height in meters squared. Waist circumference was measured in the standing position with a flexible plastic tape at the level of the umbilicus. The hip girth was measured at the widest part of the hip, and the waist to hip circumference ratio (WHR) was calculated. Bioelectrical impedance analysis was performed in the supine position after voiding (BIA-101 equipment, RJL Systems, Detroit, MI). The resistance, measured by the use of a 50-kHz, 800-µamp current, reflects principally the extracellular fluid volume (19). Systolic and diastolic blood pressures were measured sphygmomanometrically to the nearest 5 mm Hg after 5 min of supine rest. After baseline blood sampling, an oral glucose load of 100 g was given, followed by venous blood sampling for glucose and insulin every 30 min for 2 h. The serum concentration of IGF-I was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a total coefficient of variation of 6.2% at a serum concentration of 125 µg/L and 7.1% at a serum concentration of 345 µg/L. The limit of sensitivity for the assay was 13.5 µg/L. Blood glucose was measured by the glucose-6-phosphate dehydrogenase method (Kebo Laboratory, Stockholm, Sweden), and serum insulin was determined by RIA (Phadebas, Pharmacia, Uppsala, Sweden). Free T4 (F-T4) was determined by a ligand analog RIA (Amerlex M, Amersham International, Aylesbury, UK), and TSH was measured by using an immunoluminometric method (Hoechst-Behringwerke, Marburg, Germany). The total coefficient of variation was 8% for both F-T4 and TSH.

MSNA, which consists of baroreceptor reflex-controlled vasoconstrictor impulses to the muscle vascular bed and is involved in dynamic blood pressure regulation, was recorded in the postabsorptive state. Although direct recording of MSNA only represents one subdivision of the sympathetic nervous system, it correlates well with global measures of sympathetic nerve activity, such as plasma norepinephrine levels and total as well as regional (heart and kidney) norepinephrine spillover (20, 21, 22).

Multiunit recordings of efferent postganglionic MSNA were obtained with a tungsten microelectrode with a tip diameter of a few microns inserted into a muscle fascicle of the peroneal nerve, posterior to the fibular head. A low impedance reference electrode was inserted sc a few centimeters away. After acquiring a stable recording site, resting MSNA was recorded. Bursts identified by inspection of the mean voltage neurogram were expressed as burst frequency (bursts per min) and burst incidence (bursts per 100 heart beats). Details of the nerve recording technique and criteria for MSNA have been reported previously (23, 24).

Statistics

Results are presented as the mean ± SEM. Comparison between groups was performed with Student’s t test for unpaired comparison. Correlations were examined by calculating the Pearson linear correlation coefficient. Logarithmic transformation was performed on skewed data before analysis, and these are presented as geometric means. Glucose and insulin values during the 2-h oral glucose tolerance test are expressed as the area under the curve according to the trapezium rule. P <= 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In addition to being closely matched for age, gender, and BMI, the two study groups were similar in terms of WHR, body resistance, and glucose tolerance (Table 2Go).

MSNA was markedly increased in the patient group (54 ± 4 beats/min; 80 ± 3.1 beats/100 heartbeats) compared to that in the controls (34 ± 4 beats/min; 56 ± 5.4 beats/100 heartbeats). Diastolic blood pressure was also increased in the patient group and was positively correlated to MSNA (Fig. 1Go), which was not the case in the control group (Tables 2 and 3).



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  		Figure 1. Correlation between diastolic blood pressure (DBP) and MSNA in hypopituitary patients (r = 0.8; P < 0.005).

 
The patients had lower serum IGF-I and TSH concentrations (Table 2Go). When assessed for the whole study group, MSNA was inversely related to serum IGF-I (Fig. 2Go) and TSH concentrations. Within each study group, a negative correlation with similar r values was evident between MSNA and IGF-I, whereas the association between MSNA and TSH concentrations only reached significance in the combined study group (Table 3Go).



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  		Figure 2. Correlation between serum IGF-I concentrations and MSNA in hypopituitary patients (•) and healthy controls ({circ}; r = -0.59; P < 0.006).

 

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  		Table 3. Simple correlation among MSNA, diastolic blood pressure (DBP), serum IGF-I, and TSH in the whole study group, in the hypopituitary patients, and in the healthy controls

 
In a covariance analysis, the glucose and insulin areas under the curve during oral glucose tolerance test, serum IGF-I, and TSH concentrations were not able to explain the difference in MSNA between the groups, whereas the combination of serum IGF-I and TSH concentrations could (P = 0.13).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main findings of this study are that patients with hypopituitarism and untreated GH deficiency display an intense sympathetic nerve activity and that this augmented sympathetic discharge is associated with an increase in diastolic blood pressure.

An inverse relationship between MSNA and GH might be implied from previous studies; women have lower MSNA than men (25), but higher GH secretion (26); MSNA increases with age (27), whereas GH secretion decreases (28); MSNA is high during rapid eye movement sleep (29), whereas GH levels are low (30); obesity augments MSNA (31), whereas it abates GH secretion (32); hypothyroidism is associated with low GH levels (33) and high MSNA (34); in hyperthyroidism, GH secretion is increased (35), and MSNA is low (34). Furthermore, according to the present data, MSNA is markedly augmented in hypopituitary patients with untreated GH deficiency.

Peripheral features known to be associated with GH deficiency may per se elicit changes in sympathetic nervous outflow. Obesity, glucose intolerance, and insulin resistance, known risk factors for hypertension and cardiovascular disease (36), are thought to provoke changes in sympathetic nerve activity (5, 6). In the present study, factors such as BMI, central adiposity, glucose intolerance, and baseline insulin concentrations did not differ between the groups, indicating that such metabolic factors cannot account for the difference in MSNA found in this study. GH deficiency is associated with low extracellular volume (37), which could theoretically induce sympathetic activation. Body resistance, an estimate of body hydration, did not differ significantly between the groups. Although this does not totally exclude the possibility of decreased extracellular fluid volume in the present group of patients, it suggests that this is not of major importance for the difference found in MSNA.

Several central hormonal aberrations can be responsible for the sympatho-excitation seen in hypopituitary patients. The inverse relationship between MSNA and serum IGF-I concentrations suggests that the GH-IGF-I axis may be tonically involved in the regulation of central sympathetic drive. GH secretion is governed by a dual mechanism: GHRH stimulates, and somatostatin inhibits GH release. The synthesis and secretion of these hypothalamic peptides are under feedback control by GH and IGF-I (38). In GH deficiency, hypothalamic GHRH is therefore increased (39), and hypothalamic somatostatin is decreased (40). Whether such changes in the autoregulation of GH could be of importance for the sympathetic nervous system is not known. The hypothalamic secretion of GHRH can be stimulated by norepinephrine (41). Recent studies have shown a close positive relationship between subcortical norepinephrine spillover and MSNA in humans (42). The lack of GH in our patients could elicit an increase in central norepinephrine release to augment the secretion of hypothalamic GHRH and hence stimulate the release of GH. As GH release cannot be stimulated in GH-deficient patients, a positive feedback loop may arise, causing a further increase in central norepinephrine. Consequently, the increased MSNA found in our patients may be seen as a parallel phenomenon to central norepinephrine excitation.

TRH has been shown to increase MSNA in humans (8), and in patients with thyroid dysfunction, TSH levels show a positive correlation to MSNA levels (34). In the present study no correlation was found between TSH and MSNA in patients or controls (normal free F-T4 levels), but a weak negative correlation was found in the combined study group. The weaker correlation to TSH compared to IGF-I suggests that TSH is less important for MSNA in this study group. CRF, which increases somatostatin and suppresses GH secretion, causes sympatho-excitation when administered centrally in the rat (7). In fact, CRF has been suggested to be a major central sympatho-excitatory factor in humans (43, 44) and could contribute to the sympatho-excitation evident in our patient group. Although some of our hypopituitary patients received glucocorticoid and L-T4 substitution, increased levels of CRF or TRH in some patients cannot be excluded. In addition, previous transfrontal surgery and irradiation could have caused hypothalamic damages. However, the three patients previously treated in this manner and the six panhypopituitary patients with significant disturbances of the hypothalamic-pituitary-adrenal axis did not deviate from the entire group of patients.

The sympatho-excitation in our GH-deficient subjects was associated with an increase in diastolic blood pressure. No clear relationship between resting MSNA and blood pressure level exists in healthy subjects (as also demonstrated in our control group), and an increased MSNA has not been a consistent finding in primary hypertension (11, 12, 13, 14, 15). However, the parallel increases in MSNA and diastolic blood pressure in our hypopituitary patients are in line with several reports on increased MSNA in secondary hypertension, such as renovascular hypertension (45) and hypertension in chronic renal failure (46). In addition to sympatho-excitation, the formation of systemic nitric oxide, a paracrine mediator of vasodilatation, has been shown to be reduced in GH-deficient patients (47). Therefore, it can be speculated that a decrease in nitric oxide synthesis together with a centrally mediated increase in sympathetic nerve activity might give rise to the elevated diastolic blood pressure levels seen in these patients.

The novel finding of this study is that adult hypopituitary patients with untreated GH deficiency have intense sympathetic hyperactivity, equivalent to the marked sympatho-excitation seen in end-stage congestive heart failure patients waiting for cardiac transplantation (48, 49). The sympatho-excitation, which is associated with an increase in diastolic blood pressure, is probably of central origin. Improved hormonal replacement aimed at reducing sympathetic hyperactivity is therefore clearly warranted.


   Acknowledgments
 
We are indebted to Göran Pegenius and Tomas Karlsson at the Department of Clinical Neurophysiology and to Lena Wirén, Anne Rosén, Ingrid Hansson, and Sigrid Lindstrand at the Research Center for Endocrinology and Metabolism for their excellent technical assistance.


   Footnotes
 
1 This work was supported by grants from the medical faculty, University of Goteborg, and the Swedish Medical Research Council (no. 11621 and 12170). Back

Received July 23, 1997.

Revised November 21, 1997.

Revised March 4, 1998.

Accepted March 11, 1998.


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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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A. Cittadini, A. Berggren, S. Longobardi, C. Ehrnborg, R. Napoli, T. Rosen, S. Fazio, K. Caidahl, B.-A. Bengtsson, and L. Sacca
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W. Vongpatanasin, M. Tuncel, Y. Mansour, D. Arbique, and R. G. Victor
Transdermal Estrogen Replacement Therapy Decreases Sympathetic Activity in Postmenopausal Women
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E. Omerovic, E. Bollano, R. Mobini, V. Kujacic, B. Madhu, B. Soussi, M. Fu, A. Hjalmarson, F. Waagstein, and J. Isgaard
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Y. B. Sverrisdottir, B. Rundqvist, G. Johannsson, and M. Elam
Sympathetic Neural Burst Amplitude Distribution : A More Specific Indicator of Sympathoexcitation in Human Heart Failure
Circulation, October 24, 2000; 102(17): 2076 - 2081.
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B. Capaldo, G. Lembo, V. Rendina, R. Guida, P. Marzullo, A. Colao, G. Lombardi, and L. Saccà
Muscle Sympathetic Nerve Activity in Patients with Acromegaly
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K. S. Leong, P. Mann, M. Wallymahmed, I. A. MacFarlane, and J. P. H. Wilding
Abnormal Heart Rate Variability in Adults with Growth Hormone Deficiency
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W. V. Houck, L. C. Pan, S. B. Kribbs, M. J. Clair, G. M. McDaniel, R. S. Krombach, W. M. Merritt, C. Pirie, J. P. Iannini, R. Mukherjee, et al.
Effects of Growth Hormone Supplementation on Left Ventricular Morphology and Myocyte Function With the Development of Congestive Heart Failure
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