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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 344-348
Copyright © 2001 by The Endocrine Society

Original Studies

Postmenopausal Estrogen Administration Suppresses Muscle Sympathetic Nerve Activity1

Gunther Weitz, Mikael Elam, Jan Born, Horst L. Fehm and Christoph Dodt

Department of Internal Medicine I (G.W., J.B., H.L.F., C.D.), Medical University Lübeck, 23538 Lübeck, Germany; and Department of Clinical Neurophysiology (M.E.), University of Göteborg, S-41345 Göteborg, Sweden

Address correspondence and requests for reprints to: Christoph Dodt, M.D., Department of Internal Medicine, Medical University Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail: dodt{at}medinf.mu-luebeck.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 ± 1.0 yr; mean ± SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 µg/day estradiol (E2) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E2 administration significantly increased serum E2 to physiological levels (E2, 469.5 ± 51.5; P, 34.8 ± 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E2, 30.1 ± 3.0 vs. P 37.7 ± 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E2 administration supresses MSA. This effect is most likely the consequence of a direct E2 effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN WOMEN, AN increase in incidence of cardiovascular disease is linked to the menopause (1). The decline of gonadal steroids could be one pathogenetic factor for this elevated incidence of cardiovascular complications development because they have been shown to be involved in the development of arteriosclerosis. Especially estrogen exerts beneficial effects on the cardiovascular system that may, in part, be counteracted by progestins (2). Estrogens improve lipid profile (3) and also exert direct vascular effects. They induce vasodilation by an increased vascular nitric oxide production (4) and inhibit proliferative processes in the pathogenesis of artherosclerotic plaques (2). Additionally to their vascular effects, sex steroids have been shown to affect baroreflex function in animals. In ovariectomized rats, 17ß-estradiol reduces the sympathetic outflow to the kidney and the splanchnic area (5). Progesterone, on the other hand, has been shown to increase sympathetic outflow in pregnant rats due to a reduced baroreflex sensitivity (6). An inhibition of sympathetic activity by estrogen could be a contributing beneficial effect on the cardiovascular system (7). However, only few studies have examined the effect of gonadal steroids on autonomic function in humans.

In postmenopausal women, short-term administration of estradiol (E2) has been found to reduce plasma levels of epinephrine, but not norepinephrine (NE), during mental stress (8). Perimenopausal women showed a decreased total body NE spillover whereas forearm spillover of NE was unchanged after E2 administration (9). In young men, on the other hand, both decreased (10) and increased NE (11) levels during mental stress have been found after transdermal estrogen treatment. A recent study examined the changes of baroreflex sensitivity during the menstrual cycle and reported an increase of baroreflex sensitivity in phases of estrogen preponderance, whereas progesterone seemed to antagonize this effect (12). These results suggest that estrogens could exert regulatory influences on the autonomic regulation, but its mechanisms remain to be elucidated.

To further examine the E2 effects on sympathetic activity, we used microneurographic recording of sympathoneural activity to the muscle vascular bed. Muscle sympathetic activity (MSA) controls a significant portion of total peripheral resistance (13) and is the hemodynamically most important sympathetic subdivision directly accessible for intraneural recording in conscious humans (14). MSA has been shown to be positively correlated to both renal (15) and cardiac (16) NE release and can, thus, be considered to reflect the activity of large parts of the sympathetic nervous system. The resting activity of MSA is genetically determined (17) and is highly reproducible in repeated intraindividual recordings (18). Although several hormones have been found to affect MSA (19, 20, 21, 22), effects of postmenopausal estrogen administration have not been investigated. However, women before menopause have lower resting MSA than men (23) and show a lower MSA augmentation during exercise (24). Postmenopausal women seem to have a relatively stronger increase in MSA with age compared with men, which leads to the fact that MSA in this group is not different to age-matched men (25). These studies again indirectly suggest that gonadal steroids could exert regulatory influences on sympathetic nerve activity.

Against the above background, and given the fact that sympathetic hyperactivity is a widely recognized risk factor in cardiovascular disease (26), the present study tested the hypothesis that postmenopausal estrogen supplementation reduces sympathetic nerve activity. The effects of E2 supplementation for 2 days on MSA and hemodynamic parameters were investigated in 11 healthy postmenopausal women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Eleven healthy, postmenopausal women were recruited by an advertisement in a local newspaper. Menstrual bleeding had been absent for at least 2 yr, and subjects did not experience any perimenopausal symptoms (hot flushes and palpitations) for more than 1 yr (Table 1Go). Ongoing estrogen replacement therapy (ERT) (three subjects) had been stopped at least 3 months before the study. There was no evidence of disease or cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus), as determined by history and examination. The study was approved by the local ethics committee, and all participants gave written informed consent.


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  		Table 1. Anthropometric characteristics of the 11 studied subjects

 
Subjects were nonsmokers and did not take any drugs known to affect autonomic function. They were examined at 1700 h, at least 4 h after their last meal. They were asked to abstain from alcohol for 24 h and from caffeine-containing beverages 6 h before the experiment. Experimental sessions were at least 3 weeks apart. The study followed a randomized, double-blind, crossover protocol. E2 was administered transdermally, delivering ~0.1 mg E2 daily (Estraderm TTS 100; Novartis Pharma, Nürnberg, Germany). Identical patches without E2 served as placebo (P). The first patch was attached at 1100 h 2 days before the experimental procedures and was replaced by a second patch at 1100 h on the experimental day.

General procedure

Before the experiment, subjects were asked to empty the bladder. They were investigated in supine position with one leg slightly elevated to allow easy access to the superficial peroneal nerve. For blood sampling, an iv cannula was inserted into an antecubital vein. An electrocardiogram was recorded with standard chest leads. Blood pressure was recorded oscillometrically in supine subjects during the baseline period (three consecutive readings 2 min apart) and continuously from the third finger with the hand resting at heart level, using the photoplethysmographic volume clamp technique (Finapres; Ohmeda Monitoring Systems, Englewood, CO) during the complete experimental procedure. To optimize measurement of blood pressure by the finapres method, measurements were only accepted when the obtained deviation of the finapres mean blood pressure was less than ±5 mm Hg from the concomitantly obtained oscillometric mean blood pressure. Respiratory movements were monitored by a strain gauge strapped around the chest with a rubber band to control for inadvertent apneas and irregular breathing, known to affect MSA.

Multiunit postganglionic efferent sympathetic nerve activity was recorded by insulated tungsten microelectrodes with an uninsulated tip of a few micrometers. The recording electrode was inserted into a peroneal muscle-innervating nerve fascicle. A reference electrode with a larger uninsulated tip was inserted sc a few centimeters apart. The signals were amplified (gain, 50,000), filtered (band width, 0.7–2 Hz), and passed through an amplitude discriminator to obtain a mean voltage display of the multiunit nerve activity. Technical details and evidence that recorded activity is of sympathetic origin have been published previously (27). Analog signals of all recorded parameters (mean voltage neurogram, electrocardiogram, blood pressure, respiration) were digitized with a sampling rate of 200 Hz and stored on a computer disc. Signals were also printed by a Nihon Kohden 4421 Neurofax (Tokyo, Japan).

Before the patch administration, blood samples were drawn for determination of E2, progesterone, FSH, and LH, as well as electrolytes, osmolality, hematocrit, C-reactive protein, and leukocytes to evaluate the gonadal function and to exclude current disease.

On experimental days, subjects rested at least 20 min after insertion of the iv cannula. Subsequently, blood for the determination of E2, progesterone, FSH, LH, sodium, osmolality, and hematocrit was withdrawn. Blood samples were immediately centrifuged at 4 C, and serum and plasma were stored at -20 C until assay.

Experimental procedure

When a suitable microneurographic recording site had been located, data sampling started. Following a relaxation period of 15 min and blood sampling, an inspiratory apnea of maximal length (procedure trained before start of recording) was performed. After an additional 5-min period of relaxation this maneuver was followed by a 5-min resting period. Finally, subjects immersed one hand up to the wrist into ice water for 1.5 min, while breathing regularly and avoiding isometric muscle contraction (cold pressor test).

Analytical methods

MSA recordings were all analyzed by the same observer (G.W.), who was blinded regarding the administered substance. A recording was considered suitable for analysis when the maximal burst amplitude was at least three times above the baseline noise level. Sympathetic bursts were quantified visually and additionally by an analysis software that also calculated heart rate and blood pressure on a beat-to-beat basis during the experiment. Because the finapres method reliably measures relative blood pressure changes while the absolute blood pressure value is less reliably obtained, effects of E2 on blood pressure were examined by oscillometrically measured blood pressure in the supine subjects before the experiment. A mean of three different readings obtained every 2 min are reported. MSA was expressed as bursts per minute (burst frequency) and per 100 heart beats (burst incidence). The following periods were evaluated: a 5-min resting period, 15 sec before apnea and the last 15 sec of apnea, 30 sec before the cold pressor test, and the last 30 sec of the cold pressor test.

Serum sodium, serum osmolality, and hematocrit were determined by routine laboratory methods. E2 concentration was measured with commercial RIA (Diagnostic Products, Bad Nauheim, Germany). Progesterone, FSH, and LH were determined by a commercial enzyme immunological test (Enzymun-Test; Roche Diagnostics, Mannheim, Germany).

Statistics

The effects of E2 vs. P and the effects of stress maneuver vs. corresponding period before stress test were assessed by two-tailed Wilcoxon’s rank sign tests. A P value less than 0.05 was considered significant. Data are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hormones and clinical chemistry

Transdermal E2 administration resulted in significantly elevated serum E2 levels whereas FSH was suppressed (see Table 2Go). There was no significant difference in hematocrit (E2 0.390 ± 0.008 vs. P 0.385 ± 0.011), serum sodium (E2 143.2 ± 0.6 vs. P 142.8 ± 0.6 mmol/L), or serum osmolality (E2 290.2 ± 2.1 vs. P 291.6 ± 1.5 mosmol/L) after verum or placebo treatment.


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  		Table 2. Endocrine parameters (means ± SEM) during placebo and E2 sessions

 
MSA parameters

Microneurographic recording quality was adequate in all 11 subjects during the baseline period and apneas in both experimental sessions. Due to muscle tension and electromyographic artifacts, the cold pressor test recordings could be analyzed in both sessions in only eight subjects.

E2 significantly lowered burst frequency and burst incidence during the resting period (E2 30.1 ± 3.1 vs. P 37.7 ± 3.1 bursts/min, P < 0.05; and E2 43.5 ± 5.1 vs. P 53.5 ± 3.7 bursts/100 heart beats, P < 0.05) (Fig. 1Go and Table 3Go). Sympathoexcitatory maneuvers increased MSA significantly, but the increase remained unaffected by estrogen pretreatment (see Table 3Go).



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  		Figure 1. MSA burst frequency (bursts/min) and burst incidence (bursts/100 heart beats) at rest during P ({square}) and E2 () sessions. *, P < 0.05.

 

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  		Table 3. Changes of parameters during sympathoexcitating maneuvers

 
Hemodynamic parameters

E2 treatment had no significant effect on heart rate and oscillometrically measured systolic or diastolic blood pressure (Fig. 2Go). The hemodynamic responses to sympathoexcitatory maneuvers were essentially similar in verum and P experiments, although apnea induced a significant increase in diastolic blood pressure only after E2 pretreatment (Table 3Go). The cold pressor test induced a significant increase in all blood pressure parameters and in heart rate, which was independent from treatment (Table 3Go).



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  		Figure 2. Heart rate and oscillometrically measured systolic and diastolic blood pressure in 11 postmenopausal women after 2 days of estrogen supplementation () or P ({square}). SBP, Systolic blood pressure; DBP, diastolic blood pressure.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main finding of the present study is a suppressive effect of E2 in postmenopausal women on resting sympathetic nerve outflow to the muscle vascular bed. Hemodynamic parameters like blood pressure or heart rate were not affected. This excludes that the decrease in MSA is the consequence of a baroreflex activation with an elevated blood pressure causing MSA suppression (28). In our group of normotensive postmenopausal women E2 had no peripheral hypertensiogenic effects like volume retention (29). Serum sodium, serum osmolality, and hematocrit as parameters that could be changed by volume retention were not affected by short-term E2 supplementation. In fact, mechanisms leading to a slightly increased blood pressure in women on oral contraception (30) seem not be relevant in postmenopausal women on ERT. Instead, it has been reported that postmenopausal hypertension improves after E2 supplementation (31). Direct vascular effects of estrogen inducing vasodilation have been described to mediate this antihypertensive effect (4, 32). However, a pure peripheral vasodilation by E2 would have increased MSA by baroreflex mechanisms in our study. Instead, the decrease of MSA in face of an unchanged blood pressure argues in favor of a specific effect of E2 on baroreceptor function. The sensitivity of the baroreflex seems to be enhanced by E2 with the consequence that a given blood pressure is linked to a lower sympathetic outflow to the muscle vascular bed. A similar increase in baroreflex sensitivity has been described for chronic administration of 17ß-estradiol in ovariectomized rats (5). In the same study, acute administration of 17ß-estradiol suppressed sympathetic nerve activity but left mean arterial pressure unchanged again, supporting the observation of our study in postmenopausal women. An increase in baroreflex sensitivity during phases of increasing E2 concentrations (midluteal) was also described by Minson et al. (12) in a recent study on the influence of the menstrual cycle on sympathetic regulation. This E2 effect disappeared during phases of high progesterone levels that seemed to antagonize the E2 effect. The mechanism of sex steroid effects on baroreflex sensitivity remains unclear on the basis of the present studies. One could speculate, however, that E2 affects central nervous blood pressure regulating centers. Several studies have demonstrated estrogen receptors in autonomic centers of rat brain stem, such as the N. tractus solitarii (33, 34).

The unchanged blood pressure, despite a reduced sympathetic outflow to the muscle vascular bed, could have several explanations. First of all, our subjects were normotensive and the correlation between the resting MSA and the blood pressure level under "static" conditions is weak (35). That means that a tonic reduction in MSA need not automatically be followed by a decrease in blood pressure. Another explanation for the lack in blood pressure reduction could be an enhanced response to vasoconstrictive substances like catecholamines (36) or their increased concentration. A reduced reuptake of catecholamines due to estrogen administration has been described (37). Recently, Sudhir et al. (9) reported a significant decrease in total NE spillover in perimenopausal women experiencing climacteric symptoms after administration of E2 for 8 weeks. However, unlike the total NE spillover, NE spillover to the muscle vascular bed of the forearm was not affected. The amount of transmitter spillover to the circulation depends on the degree of NE release to the synaptic cleft, from neuronal and extraneuronal reuptake of the transmitter and from regional blood flow (13). The fact that our study observed a reduction of the sympathetic outflow to the muscle vascular bed while Sudhir did not report any change in spillover from this region could indicate that reuptake and, thus, plasma clearance of the catecholamine is diminished by E2; thus NE plasma spillover could be unchanged or even enhanced despite a decreased neuronal NE release.

The results underline the importance of E2 in the regulation of the sympathetic nervous system in women. They suggest that the previous finding of lower MSA in women compared with age-matched men (23, 38) could, at least partly, be explained by hormonal effects on central autonomic regulation. Such influence could also explain the accelerated increase of MSA with age after menopause (25) and indicate that this increase could be reversed with hormonal replacement therapy. However, one limitation of our study is that we administered transdermal E2 for only 2 days, and we cannot predict the effects of long-term ERT on the regulation of the sympathetic nervous system. He et al. (5) described an acute (within 15 min) suppression of sympathetic outflow after iv injection of E2 whereas chronic E2 administration induced an increase in baroreflex sensitivity without any change in baseline sympathetic activity. These findings underline that E2 effects on sympathetic regulation in postmenopausal women may depend on the duration of the replacement therapy.

The sympathosuppressive effect of E2 in our study was restricted to resting conditions. MSA responses to voluntary apneas and cold pressure tests were not affected, indicating a preserved reactivity of these vasoconstrictor nerve fibers under ERT. However, these observations cannot be extrapolated to other sympathoexcitatory conditions, such as mental or physical stress. Several studies have examined the responses of the autonomic system to the latter stressors in relation to gender and hormonal status. In a study on premenopausal women and age-matched men, women demonstrated an attenuated increase in blood pressure and MSA to static exercise compared with the male group (24). Mental and physical stress responses have also been reported to be affected by the hormonal status (pre- and postmenopausal) and the phase of the menstrual cycle (39). Estrogen administration reduced the NE response to mental stress in postmenopausal women and young men (3, 40). These findings indicate that sympathosuppressive effects of E2 are probably not restricted to resting conditions and could also occur during mental and physical stress, whereas other sympathoexcitatory reflexes during apnea and cold pressure are not affected by the steroid.

In conclusion, our study demonstrates a distinct reduction of sympathetic nerve activity in postmenopausal women after short-term transdermal ERT. This effect is most likely a consequence of a central nervous suppression of sympathetic nerve activity to the muscle vascular bed. The sympathoinhibitory property of physiological E2 levels could explain the gender-specific lower MSA in premenopausal women and might contribute to the beneficial effects of ERT in the primary prevention of arteriosclerotic cardiovascular disease.


   Acknowledgments
 
We are indebted to Dr. M. M. Müller for support and critical review of this work. The excellent technical assistance of Christiane Zinke is gratefully acknowledged.


   Footnotes
 
1 Supported by a grant from Novartis Pharma GmbH (Nürnberg, Germany). Back

Received January 6, 2000.

Revised September 1, 2000.

Accepted September 29, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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