Gender, sex hormones and autonomic nervous control of the cardiovascular system

Time for primary review 42 days. The autonomic nervous system is of importance in the natural history and treatment of a number of pathophysiological states involving the cardiovascular system. These include hypertension and diseases of the vasculature as well as myocardial ischaemia and cardiac arrhythmias. Gender differences in the incidence and clinical course of a range of cardiovascular states are also well recognised. Both short and long term prognosis after myocardial infarction are worse for women than men [1–4], whereas women with non-ischaemic cardiomyopathy have improved survival [5,6]. In addition to the well known difference in age of presentation of coronary heart disease, women are more likely to suffer from Raynaud's phenomenon, and to experience presyncopal or syncopal episodes. An appreciation of gender differences in the structure and function of the autonomic nervous system is therefore important to a full understanding of a number of common and important clinical presentations [7]. Gender differences in the autonomic nervous system may be present because of developmental differences or due to the effects of prevailing levels of male and/or female sex hormones. Such prevailing hormone levels may also produce differences between pre- and post-menopausal women and amongst pre-menopausal women at different phases of the menstrual cycle, which is characterized by oestrogen secretion in the late follicular (pre-ovulatory) phase followed by a secondary phase of secretion in the luteal (post-ovulatory) phase. Progesterone secretion occurs during the luteal phase. Differences in the autonomic system may be due to differences in afferent receptor stimulation, in central reflex transmission, in the efferent nervous system and in post synaptic signaling. At each of these potential sites of difference, there may be effects due to different size or number of neurons, variations in receptors, differences in neurotransmitter content or metabolism as well as functional differences in the various components of the reflex arc. As indicated in the Introduction there are multiple potential sites in the autonomic nervous system which may be subject to gender related differences. Consequently the examination of gender differences may require use of a wide range of experimental and clinical methodologies. In this section brief mention will be made of techniques specifically related to this question. Neurotransmitter release from efferent terminals may be estimated from plasma levels, particularly for the sympathetic nervous system by measuring plasma noradrenaline (NA) and adrenaline levels or their urinary excretion. Such methods, which are available for both animal and human studies, do not account for clearance or regional changes that may however be estimated from determination of transmitter spillover [8]. It is also possible to measure extracellular concentrations regionally from microdialysis. Estimation of cholinergic neurotransmission by assay of acetylcholine is more problematic due to the activity of cholinesterase leading to rapid hydrolysis. Neural firing patterns and frequency can be determined by direct recording in animals and from accessible sites in man. In animal studies these may include both afferent and efferent fibre recording of both divisions of the autonomic system. In human studies they have been restricted to efferent fibre recording of accessible sympathetic nerve fibres. The efficacy of neurotransmitter release can be determined by measuring physiological and/or biochemical post-synaptic responses known to be mediated, at least in part, by the autonomic nervous system. Pharmacological blockade with agents administered either centrally or systematically may allow physiological responses to be attributed to sympathetic or vagal activity. Certain physiological changes, such as the pattern of variation in heart rate and blood pressure, may allow conclusions about overall balance of sympathetic/parasympathetic responsiveness. Such measures are particularly useful in humans as they may be obtained non-invasively and provide an integrated assessment of autonomic function incorporating both pre and post synaptic aspects of control. Thus a relative preponderance of high (respiratory) frequency (HF) over low (0.1 Hz) frequency (LF) spectral power of heart rate analysed in the frequency domain is indicative of a parasympathetic preponderance [9,10]. Changes in LF power per se are less specific indicators of sympathetic autonomic modulation [8–10]. Analysis of the baroreflex provides information on the integrated reflexes of sympathetic and vagal nerves in controlling heart rate and blood pressure. The baroreflex can be assessed by frequency domain analysis of the relationship between heart rate and blood pressure variability or by perturbing pressure receptor afferent activity and measuring reflex heart rate and blood pressure responses. In humans, resting plasma concentrations and urinary excretion of NA and adrenaline are generally not different between males and females [11–13] however, males have been found to have higher resting sympathetic nerve activity to muscles, as determined by micro-neurography [13,14] particularly below the age of 50 in most [15,16] but not all studies [17]. Variations in the plasma concentration of NA have been found during the menstrual cycle [18,19] and muscle sympathetic nerve activity was also higher in the mid-luteal than the early follicular phase [19] Numerous human studies have examined heart rate variability and related indices of sympathetic/parasympathetic balance. The majority of studies have found women to have a lower LF/HF power ratio than men, suggesting a preponderance of vagal over sympathetic responsiveness [20–23]. Higher LF power in men has been found in several studies [22–26]. These data suggest that males have a preponderance of sympathetic over vagal control of cardiac function compared with females. Finger blood flow was reduced in response to infused adrenergic agonists in men but not women [27]. Forearm vasoconstrictor responses to intra-arterial NA were also significantly less in women than in men [28]. A subsequent study [29] indicated that an enhanced response to β-AR stimulation in premenopausal women accounts for the reduced vasoconstrictive response seen when NA is infused alone. In line with the enhanced responses seen in men, tail arteries from male rats show greater vasoconstriction to perivascular stimulation than do female rats [30]. The reactivity of isolated aortic rings to catecholamines is greater for male than for female rats [31]. However male responses are similar to those of ovariectemised females suggesting an inhibitory effect of oestrogen on vasoconstrictory responses [32]. Systemic responses to NA but not electrical stimulation are reduced in males with orchidectemy. Treatment with testosterone, but not with oestrogen, in castrated rats enhanced the vasopressor action of NA [33]. Vasoconstrictive effect of neuropeptide Y (NPY), a sympathetic co-transmitter, is more pronounced in male than that in female rats and NPY release and actions can be upregulated by testosterone but down-regulated by oestrogen [34,35]. In contrast to tail arteries and aorta, responses to electrical field stimulation in mesenteric resistance vessels are greater in young female rats compared with males whereas there is no difference in older animals [36]. Other studies have shown that α-AR affinity and vascular catecholamine sensitivity increase in small mesenteric arteries of female and oestrogen treated male rats compared with native male rats [37]. However testosterone did not affect α-AR density or affinity in female rats [37]. A number of studies have reported that men show a greater response in systolic blood pressure to a number of cardiovascular stressors [38,39]. Some but not all studies have however found gender differences in the response to valsalva and deep breathing [40–42]. Interpretation of the results of human responses to stressors requires consideration that women apparently perceive the relative strength of stressors differently to men [43]. The increase in plasma NA in response to head up tilt was significantly greater in older males than older females [44]. Heart rate variability analysis demonstrated that in response to tilt young females yielded lower power at LF and lower LF to HF ratio than the younger men. In a study of healthy young men and women, rise in systolic blood pressure was more marked for men after a range of different activities including treadmill walking, rowing and cycling [12]. Women have a blunted adrenaline rise in response to posture and moderate physical activity in some studies [45,46] but an enhanced adrenaline response in others [47]. Urinary excretion of NA and adrenaline, however, were not different between males and females following exercise [12] whilst NA spillover in response to exercise was greater in men than women [48]. As discussed, neuroendocrine responses to exercise have produced variable responses with some studies showing reduced or similar catecholamine responses in women relative to men [47,49,50]. Some of these inconsistencies may have arisen because of variation in plasma glucose and insulin levels. To prevent this in the studies of Davis et al. [51] subjects were infused with dextrose to maintain plasma glucose at euglycaemic levels during exercise. With such conditions systolic blood pressure and plasma levels of NA, adrenaline and pancreatic polypeptide all increased substantially more with exercise in males than females. Gender differences are also a result of differences in metabolic stimulation. In the study of Ettinger et al. [52] microneurography and metabolic measurements were performed at rest and after repetitive hand grip exercise performed under non-ischaemic and ischaemic conditions. This design permitted study of the role of metaboreceptor activated autonomic reflexes associated with ischaemic metabolite accumulation. In these studies, it was shown that the smaller rise in nerve firing rate in response to exercise in women was probably the result of a smaller change in intracellular pH and other metabolites, and not as the result of differences in muscle mass, leading to reduced mechanoreceptor mediated afferent stimulation. Activation of neuroendocrine responses are an important counter regulation to hypoglycaemia. Responses to hypoglycaemia have been compared in healthy young male and female volunteers [53]. The threshold levels for neurohumoral responses were similar in men and women. However, increases in sympathetic nerve activity once threshold hypoglycaemic levels have been reached, were greater in men than women. Similarly there were greater increases in plasma adrenaline levels. The differences in neurohumoral response without difference in hypoglycaemic threshold was interpreted as a difference in central or effector sympathetic mechanisms. Healthy control women and women with type 1 diabetes have a significantly reduced sympathetic nervous response to hypoglycaemia than men. Interestingly, however, hypoglycaemia is not more prevalent in women with type 1 diabetes than in men [54]. In an attempt to resolve this paradox, Davis et al. [17] studied the effects of antecedent hypoglycaemia which is known to blunt subsequent neuroendocrine responses to a further hypoglycaemic episode. Such blunting was much less marked for women and only occurred after more severe antecedent hypoglycaemia. Differences in blunting were also evident for pancreatic polypeptide, a marker of vagal activity. In a clinical study measuring muscle sympathetic nerve activity [14], the latency for achieving peak response to isocapnic hypoxaemia was significantly shorter in women compared with men. Recovery from hypoxaemia was also more rapid in women than men. Conversely in response to hyperoxaemia sympathetic nerve activity decreased significantly only in men. In keeping with the more rapid responses seen in women, female rats show enhanced dopamine and NA turnover in carotid body and brainstem NA cell groups in response to hypoxia compared with males [55]. Responses to direct cooling may result from a number of mechanisms including direct effects on cutaneous, venous α-AR [56]. Responses to cooling a contralateral limb are believed to arise by thermoreceptor stimulation leading to increased sympathetic neural activity which is more marked in premenopausal women than men and in premenopausal than postmenopausal women [57,58]. In response to mental arithmetic and deep inspiration hand and skin blood flow was reduced in men but, paradoxically increased in women. In a series of ingenious experiments involving whole body heating or cooling to increase or reduce central sympathetic outflow to the hand, Cooke at al. [59] showed the responses to mental arithmetic depended on the prevailing level of sympathetic tone to resistance vasculature. Thus, the differences in resting blood flow between men and women, which probably account for differences in Raynaud's phenomenon, are not due to local structural changes which limit maximum flow but to the basal differences in central sympathetic tone. Similarly evidence against structural factors limiting flow is that forearm hyperaemic flow is actually greater in women than men [60]. Also in keeping with these findings is that female patients with Raynaud's syndrome show a paradoxical vasodilatation with mental stress [61]. Huikuri et al. [62] found women to have reduced baroreflex sensitivity, measured during the valsalva manoeuvre. In post menopausal women, those on hormone replacement therapy (HRT) had higher baroreflex sensitivity than those not on HRT. Changes in baroreflex sensitivity during the menstrual cycle and with the use of the oral contraceptive have also been examined [19,63]. Sympathetic but not vagal cardiac baroreflex sensitivity was greater during the early follicular than the mid-luteal phase and both were greater in the low hormone (placebo) compared with the high hormone phase of oral contraceptive use. Compared with intact female animals, ovariectomized animals showed enhanced sympathetic activation and attenuated baroreflex sensitivity or vagal tone and such differences were minimized by oestrogen treatment [64,65]. The inhibition in lumbar sympathetic activity induced by cardiopulmonary receptor stimulation in rats with sino-aortic baroreceptor denervation was significantly greater in female than male animals [66]. Human and animal data indicates significant differences exist between males and females in basal function of the autonomic nervous system. There is consistent data to suggest males have higher sympathetic, and females higher parasympathetic, cardiac autonomic activity. Sympathetic nerve firing rates, at least to leg muscles, are more pronounced in men than women. However, sympathetic outflow to the forearm seems to be greater in women. In the majority of vascular beds, basal sympathetically mediated vasoconstriction is greater in men than women. However, animal data suggests that the converse may be true in the mesenteric circulation. Furthermore, there are clear gender differences in the autonomic response to stressors which vary according to the nature of the stress. Cardiac responses to isoprenaline were similar in older males and females but greater in younger males than females indicating a greater age-dependent decline in function in males than females [67]. Below the age of 50 muscle sympathetic nerve activity was significantly greater in men than the women but no differences between genders were noted for older subjects [15]. In the study of Kuo et al. [24], the percentage LF power was significantly higher in the younger males than the younger females whilst the percentage HF power was significantly higher in the younger females than the younger males. The gender differences were largely lost after 55 years of age. Yamasaki et al. [22] also found a decline with age for both HF and LF power. The decline with age was more marked for men than for women In obese men and women subjected to severe weight restriction, plasma adrenaline increased more in men than women [68]. In a study of healthy older men and women [69], NA spillover was found to be significantly higher in men than in women. NA spillover was positively related to waist circumference again suggesting that distribution of body fat is an important determinant of sex differences in sympathetic activity. In the study by Jones et al. [16], increased muscle sympathetic nerve activity was also found in young males compared with young females. There was significant correlation for both males and females between muscle nerve activity and percentage body fat. However, for any given percentage body fat, nerve activity was greater in the males. Muscle sympathetic nerve activity also was strongly correlated with the waist to thigh ratio. An adjustment for waist-to-thigh ratio eliminated gender difference in sympathetic nerve activity [16]. Thus, this study suggests that at least part of the sex difference in sympathetic neural activity is associated with the different pattern of fat distribution between the genders Myocardial ischaemia may activate both vagal and sympathetic afferent fibres within the heart. A predominance of vagal activation following myocardial ischaemia may have both beneficial and harmful effects and experimental studies have shown that augmented vagal activity is antifibrillatory during myocardial ischaemia [70]. However, there are also data to suggest that extreme vagal activation results in asystole or haemodynamic instability [71]. There seems to be a female preponderance of unexplained syncope amongst middle-aged patients with myocardial infarction [72]. Furthermore, women had a higher risk of hypotensive and bradycardia reactions following admission with myocardial infarction [73] and a higher risk of acute haemodynamic complications following an acute angioplasty [74]. Airaksinen et al. [75] analysed changes in heart rate, heart rate variability, blood pressure and ventricular ectopy in 114 men and 65 women undergoing single vessel coronary artery angioplasty with a short episode of ischaemia. Although there were no significant differences at baseline, heart rate variability during coronary artery occlusion was higher in women than men. Significant severe bradycardia and hypotension was much more common in women than men. These findings are in agreement with an experimental study in rats showing a significant early in heart rate and pressure in female rats after coronary artery [7]. infarction induced by sympathetic activation were more severe in male than female rats The relative preponderance of sympathetic parasympathetic responsiveness in indicated in the seems to be lost with age. differences in sympathetic activity are related to body fat distribution with sympathetic activity found with type The female preponderance of parasympathetic activity may female resistance to ischaemic but at the of increased to of the mechanisms for gender and effects on the autonomic nervous system have generally animal or Some sex differences in the autonomic nervous activity are present the distribution of in the between the of male and female rats female rats have and activity is higher in males than females Although information is evidence suggests that have significant effects on the efferent nerves and of effector that to hormone are mediated of to and to and of the with to rapid of actions with changes in due to in of and oestrogen receptor have been in in the regulation of cardiovascular function sites for oestrogen, and testosterone are also present in these It has been shown that sex affect multiple aspects of central or of oestrogen increased vagal tone and sympathetic efferent activity in ovariectomized female and male rats and these actions were blunted by with oestrogen receptor indicating a central effect of oestrogen increased the density and affinity of The and clearance of are by sex hormones. the catecholamine et al. that male rats had a significantly NA than females in and measured by levels are higher in male than female reduced after and by testosterone replacement cholinergic neurons, the activity of and are higher in female than male rats the activities of and and reduced acetylcholine content in and these changes were by of oestrogen As in centrally neurons, the and metabolism of catecholamines and in are also by from females more than those from males Treatment of ovariectomized rats with oestrogen and increases the density of β-AR and in the heart and in nerves stimulation of efferent vagal nerves induced more pronounced bradycardia in female than in male but the response to did not between the indicating a of release by nerve activation in female There were however no differences in response to efferent vagal nerve stimulation between intact and ovariectomized female rats Neurotransmitter release is by inhibitory receptor and on the α-AR density and activity in a number of are higher in women direct of receptor density is some studies higher levels of density or sensitivity in in women than men and density correlated significantly with variations in oestrogen levels However, such differences were not by others showed a more pronounced inhibition of NA release in heart apparently due to a higher density and/or activity in females Such difference after There may also be a role for which is produced in response to oestrogen and is known to NA release of catecholamines after release on and by specific It is not clear there are gender differences in this some studies indicated a more clearance of adrenaline in females than males may also the activity of and effects of may also to modulation of the autonomic nervous system. In with of sympathetic density in increased by nerve and and sex differences in levels of have been reported a effect in and the vascular and have shown that in by oestrogen from In male is associated with reduced content and release of NA and this is not present in females studies are to the of this action of oestrogen and role in in autonomic function under and conditions. data indicates the of for in the including in for the of the autonomic nervous system. of oestrogen parasympathetic activity. In there is evidence that testosterone NA and NPY as well as activity of NA oestrogen the activity of and with also that oestrogen is associated with increased and release of these are consistent with the in parasympathetic responsiveness is greater in females and sympathetic responsiveness greater in males. that oestrogen may also nerve density and survival effects on nerve In the effects of oestrogen may age related decline in autonomic activity is more evident in males than females. The autonomic nervous system a role in the regulation of the cardiovascular system under both physiological and pathophysiological conditions. There is evidence of gender difference in the of the autonomic including specific effects of both male and female sex as in As a at least in humans, there is a preponderance of sympathetic mediated responses in males and of parasympathetic in females related to gender during human These a role in the course of and prevalent of differences under physiological and pathophysiological conditions and the by autonomic nervous system autonomic nervous coronary artery females. of differences under physiological and pathophysiological conditions and the by autonomic nervous system autonomic nervous coronary artery females.