Psychological Sweating: A Systematic Review ...

Review Skin Pharmacol Physiol 2013;26:92–100 DOI: 10.1159/000346930

Received: September 27, 2012 Accepted after revision: December 27, 2012 Published online: February 20, 2013

Psychological Sweating: A Systematic Review Focused on Aetiology and Cutaneous Response M. Harker Unilever Research & Development, Port Sunlight, UK

Key Words Catecholamines · Emotional sweating · Innervation · Malodour · Stress

Abstract Psychological sweating in response to emotive stimuli like stress, anxiety and pain occurs over the whole body surface, but is most evident on the palms, soles, face and axilla. This is primarily a consequence of high eccrine sweat gland densities at these body sites. Cholinergic innervation is the primary effector eliciting activation of eccrine sweat glands during periods of acute psychological stress. A dual innervation pathway for eccrine glands (adrenergic and cholinergic) may augment increased sweat output, but this remains to be substantiated. Circulating catecholamines appear not to mediate eccrine gland activity, but may play a role in the activation of apocrine sweat glands. Apocrine sweating is strongly regulated by psychological stimuli and localised to those body sites hosting apocrine glands, with adrenergic peripheral pathways being the primary effector. Accordingly, in the axilla psychological sweating leads to increased sweat output and malodour formation, although this form of sweating at this body site is not observed until puberty. Copyright © 2013 S. Karger AG, Basel

© 2013 S. Karger AG, Basel 1660–5527/13/0262–0092$38.00/0 E-Mail [email protected] www.karger.com/spp

Introduction

Sweating in response to exercise or high environmental temperature plays an important role in thermoregulation and is effected by eccrine sweat glands. Psychological sweating, also referred to as emotional sweating, in response to emotive stimuli like stress, anxiety, fear and pain occurs over the whole body surface, but is most evident on the palms, soles, face and axilla, and is effected by both apocrine and eccrine sweat glands [1, 2]. Initiation of this form of sweating is not dependent on thermal loading. Apocrine glands exist at birth but do not become active until puberty and, although their specific function is unclear, they are known not to be involved in thermoregulation in humans [3]. Due to the occluded nature and ample supply of eccrine, apocrine sweat and sebum, the human axilla supports a dense cutaneous population of micro-organisms. The metabolic activity associated with this large microbial results in the generation of axillary malodour. Body odours and excessive sweating are perceived as being socially unacceptable conditions known to erode self-confidence and reduce the quality of life. As a consequence many individuals adopt compensatory behaviours to prevent social stigma [4], the most common form of which is the application of an antiperspirant or deodorant. Mark Harker Unilever Research & Development, Quarry Road East Port Sunlight CH63 3JW (UK) E-Mail mark.harker @ unilever.com

Table 1. Eccrine sweat gland densities at different body sites (/cm2)

citied from different references Region

Wilke et al. [7]

Hwang and Baik [10]

Szabó [11]

Palms Sole Forehead Forearm Abdomen Upper arm Axilla Thigh Face Back

644 – – 134 127 90 68 57 59 –

248 ± 92 262 ± 98 200 ± 80 112 ± 53 81 ± 30 99 ± 42 90 ± 38 125 ± 41 84 ± 59 112 ± 32

– 620 ± 120 360 ± 50 225 ± 25 190 ± 5 150 ± 20 130 ± 25 120 ± 10 320 ± 60 160 ± 30

Numerous reviews regarding the structure, function and physiology of both eccrine and apocrine glands are available [5–7]. However, only those aspects of sweat gland biology pertinent to psychological sweating will be included in the current review. As the occurrence of a third type of sweat gland, the ‘apoeccrine’ gland, remains highly controversial, the potential role of these glands in psychological sweating remains to be established and will therefore not be discussed [8].

Sweat Glands – Distribution

Eccrine sweat glands can be found over the whole body surface (1.6–4.0 million) with only a few exceptions: lips, nail bed, nipple, inner preputial surface, labia minora, glans clitoris and glans penis, with the highest sweat gland densities found on the palms and soles (table 1) [9–11]. The human apocrine gland develops from the hair anlagen in the embryo, and is therefore always associated with the hair follicle [12]. Consequently, the majority of apocrine sweat glands can be found in mainly hirsute areas such as the axillae, perineal and areolae regions [7].

Sweat Glands – Innervation and Pharmacology

Eccrine sweat glands are innervated by postganglionic sympathetic fibres of unmyelinated class C type via acetylcholine [5]. However, eccrine sweating can also be stimulated by the intradermal injection of adrenergic agonists [13], and adrenergic neurons have been observed in close proximity to these glands [14]. Nevertheless, Psychological Sweating

physiological sweating, either psychological or thermal, appears to be predominantly cholinergic as it is inhibited by atropine [15]. Denervation of the nerves supporting eccrine glands abolishes gland function completely [16]. This data coupled to the fact that Botox, a potent neurotransmitter antagonist, also severely impairs sweat gland function indicates that a functioning nerve supply is required for normal function [17], and that humoral control of sweating plays little or no role in the primary stimulation of eccrine sweat glands. Although eccrine sweat glands respond to the intradermal injection of catecholamine agonists, quantitatively this adrenergic sweat response represents only 20–50% of that elicited by acetylcholine [18–21]. The reason for a dual sympathetic neural control mechanism is unclear but has been postulated as a mechanism for elevating intracellular cyclic adenosine monophosphate (cAMP) levels in response to adrenergic innervation [22]. The exact function of cAMP in mediating the sweat response is unknown, but is thought to play some role as an intracellular mediator in response to β-adrenergic stimulation [6]. However, there is no evidence to support the theory of adrenergic stimulation amplifying cholinergic sweat production in humans [5]. In addition to control from higher centres, there is evidence that local regional sweating may be stimulated by axon reflex. If acetylcholine is iontophoresed into the skin, sweating is initiated not only in the area surrounding the treated site but also extends radially beyond this point for several centimetres [23, 24]. A variety of other neurotransmitters and humoral agents are known to modulate the secretory function of the eccrine sweat glands. Sweat glands have been shown to be responsive to vasoactive intestinal peptides (VIPs) [25], proteinase-activated receptors (PAR-2) [26], calcitonin gene-related peptide [27], substance P [27], galanin [28] and adenosine triphosphate [29]. PAR-2, adenosine triphosphate and galanin were all shown to increase intracellular Ca2+ levels in isolated sweat glands or the eccrine sweat gland cell line NCL-SG3, whereas calcitonin gene-related peptide amplified axon reflex sweating on human skin when administered in combination with acetylcholine. VIPs may have a role in maximizing intercellular cAMP accumulation, together with acetylcholine. In contrast to the other neuropeptides studied, substance P had an inhibitory effect on methacholine-induced sweating [30, 31]. Although eccrine sweat glands respond to a range of pharmacological agents, these play a relatively minor role in modulating gland activity compared to acetylcholine.

Skin Pharmacol Physiol 2013;26:92–100 DOI: 10.1159/000346930

93

The responsiveness of axillary apocrine glands to both adrenergic and cholinergic agents in vivo has been observed [32]. Earlier work indicated that the apocrine secretion is induced only by adrenaline but not by pilocarpine [33]. However, Aoki [32] challenged this view by demonstrating that the milky apocrine sweat can be induced around the hair follicle following intradermal injection of pilocarpine as well as adrenaline. Experiments on isolated axillary apocrine glands demonstrated that the apocrine glands respond to both cholinergic and adrenergic agonists, and that β-adrenergic stimulation is generally more potent than the α-adrenergic counterpart [34]. The responsiveness of the secretory cells to both cholinergic and adrenergic agonists suggests dual activation of apocrine sweat glands. This contention is supported, if not proven, by observations that both catecholamine-containing and cholinesterase-positive nerve fibres surround axillary apocrine glands [14]. The secretory portion of the apocrine gland has been shown to express β2- and β3-adrenoceptors close to the basolateral membrane and purinoceptors in the myoepithelial cells (fig. 1) [3]. These adrenoceptors potentially mediate apocrine sweating in response to stimulation by catecholamines. Contraction of the myoepithelial cells surrounding the glands potentially ‘squeezes’ out the preformed sweat into the follicular infundibulum, this contraction being mediated by adrenergic but not cholinergic agonists [35].

Psychological Sweating

Exposure to acute psychological stress initiates immediate physiological and behavioural responses. The socalled fight-or-flight response involves a network of activated mechanisms designed to promote survival in a situation of danger and maintain homeostasis [36, 37]. Psychological stress causes the rapid general discharge of the sympathetic nervous system resulting in the release of catecholamines including adrenaline and noradrenaline, which lead to increases in heart rate, respiration and blood pressure [36]. The hypothalamic-pituitary-adrenocortical (HPA) axis is activated in a slightly slower timeframe, leading to the elevation of circulatory glucocorticoids, including the classical stress hormone, cortisol [37]. Circulating glucocorticoids act at their receptors throughout the body to mobilise stored energy, maintain vasomotor tone, and provide feedback inhibition to further glucocorticoid release [38]. Prolonged stimulation of the HPA axis activates the immune system, leading to 94


Basolateral membrane

Myoepithelial cell

Secretory cell

Apical membrane Apical blebs

Gland lumen

10 μm

Fig. 1. Immunohistochemical staining for β2-adrenoceptors in the secretory region of a human axillary apocrine sweat gland [for experimental details about the image, please refer to 3].

mild inflammation [39] through the release of inflammatory mediators including cytokines, free radicals and prostaglandins [38]. Sweating across the whole body, which is most evident on the palm, sole, face and axilla, is also elicited at these times [40]. The same excitatory stimulus (e.g. stressor) can have profoundly different effects on the activation of autonomic, neuroendocrine and immune stress responses between individuals. The level of stressor required to initiate these physiological responses, including sweating, will be dependent on individual responses and is not generic across the population [36]. Sweating on palmar and plantar skin in response to changes in behavioural states has been demonstrated in infants at around 10 days old [41], whereas in the axilla psychological sweating is not initiated until puberty [4]. Psychological sweating is particularly problematic in the axilla due to the occlusive nature of the site, meaning that sweat cannot readily evaporate once formed, so that it accumulates and becomes noticeable both to the individual and others [4, 42]. Concomitant activation of the apocrine glands results in the formation of malodour, which can also be perceived by the self and others in the vicinity [42]. This cascade of sweat secretions and self-perceived awareness of sweat and malodour sets up an escalating and self-sustaining cycle, in which increased anxiety results in more sweating, which in turn leads to more anxiety and so on. Eccrine and apocrine sweat glands in axillary skin can be seen in figure 2. Harker

500 μm

sured in response to various physical and psychological stimuli, but no sweat stimulation was elicited. After neurological improvement associated with diminution of amygdala lesions, determined by magnetic resonance imaging, normal sweat responses were restored [49, 50]. The direct electrical stimulation of the human amygdala, hippocampus and anterior cingulate gyrus ipsilaterally was reported to elicit electrodermal responses, with the stimulation of the amygdala evoking the most prominent reaction [51]. The origin of psychological sweating using sympathetic skin sweat response (SSSR) was investigated during mental stress tasks in 2 healthy subjects. The results indicated that activation of the frontal cortex, the hippocampus and the amygdala corresponded to an increased SSSR [52].

Fig. 2. Eccrine and apocrine sweat glands in axillary skin. Cross-

section through eccrine (thin arrows) and apocrine (thick arrows) secretory coil stained with P2Y2 antibody for enhancement of visualisation [for experimental details about the image, please refer to 3].

Central Motor Control of Psychological Sweating

The exact mechanism of the central pathway responsible for psychological sweating is still unclear. Boucsein [43] suggested that electrodermal activity is regulated by the limbic system, motor system (the premotor cortex and basal ganglia) and reticular formation. Thus, it is possible that several brain structures participate in psychological sweating. Although, the amygdala has been proposed to be the key brain centre involved in psychological sweating. The amygdala, which is an important part of the limbic system, is a brain structure critical for memory and is associated with certain psychological conditions, psychological behaviour [44], social behaviour [45] and neuroendocrine and autonomic function [46]. Amygdalectomy in monkeys has been demonstrated to attenuate or abolish electrodermal activity, which reflects psychological sweating in humans [47]. Further studies investigating the functional neuroanatomical system of psychological sweating in humans have also reported that psychological sweating is related to the amygdala. A 19-year-old patient with a past history of herpes simplex encephalitis showed a reduced level of electrodermal responses to mental stress following bilateral amygdalotomy [48]. In patients with bilateral restricted amygdala lesions caused by idiopathic subacute limbic encephalitis, skin electrodermal activity was meaPsychological Sweating

Localisation of Psychological Sweating

One widely held belief about sweat gland responsiveness is that sweating induced by psychological stimuli is restricted to discrete regions of the body, in particular the glabrous (hairless) skin surfaces (e.g. palms and soles) [53]. However, more compelling data support the notion that emotion-evoked sweating is not limited to particular regions of the body but is a generalised phenomenon, although such sweating (or corresponding electrodermal activity) may only be visible on the palms, soles, axilla and face at normal room temperatures [40, 54–56]. Given the regional differences in sweat gland density outlined previously, it is possible that measurable sweat responses are more readily obtained from the palms, feet and axilla, where sweat glands are more numerous compared to other body sites. In 1 study in which sweat gland density was considered [2], palmar and plantar surfaces exhibited no greater responsiveness to psychological stimuli than did other regions of the body. The investigators instead found emotion-evoked sweat response to be proportional to the number of sweat glands in each region at two different temperatures (26 and 29 ° C). Given the propensity of glabrous skin surfaces to sweat profusely in response to psychological stimuli, they are relatively unresponsive to moderate exercise, in terms of increased sweat output compared to the majority of body sites [57]. Apocrine sweating is limited to those areas containing apocrine sweat glands, i.e. the axilla and inguinal region, and hence it is only these regions which are responsive to psychological stimuli in the case of apocrine sweat secretion.


95

Innervation and Pharmacology of Psychological Sweating

The release of catecholamines in response to psychological stimuli has resulted in a general consensus that these hormones are primarily responsible for eliciting the psychological sweating response, particularly at palmar and plantar sites [58, 59]. In addition, others report that some or all of the sympathetic fibres innervating those locations are adrenergic [60–62] or that circulating catecholamines stimulate sweat gland activity directly [63]. Adrenergic fibres are much more sparsely distributed than cholinergic fibres, but have been found in close proximity to sweat glands throughout the skin’s surface (including non-plantar and non-palmar sites) [3]. However, there is ample evidence that adrenergic activation of eccrine sweat glands of local neural origin cannot by itself be responsible for sweating or electrodermal responses [16]. The blockade of local norepinephrine release results in no decrease in skin resistance in response to a variety of psychological stimuli [16]. Atropine, however, blocks all responses under the same conditions [64]. These results suggest that the primary neurotransmitter for mediating (at least part of) the psychological eccrine sweating response is cholinergic in origin [56]. A role for catecholamines in mediating the psychological sweating response at glabrous skin sites cannot be totally ignored. Cutaneous arterioles in glabrous skin are innervated exclusively by noradrenergic sympathetic vasoconstrictor nerves [65–68]. The observation that cutaneous arterioles in plantar and palmar skin are heavily innervated by adrenergic nerves [66–68], which may also innervate adjacent sweat glands [69], leads to the possibility that sweat gland innervation at these regions is influenced by processes mediating cutaneous blood flow in addition to cholinergic stimulation [69, 70]. Such an observation provides a possible mechanism for the increased adrenergic augmentation of sweat gland activity in these regions compared to other body sites, including in response to acute psychological stress. In non-glabrous skin, reflex changes in skin blood flow are mediated by two branches of the sympathetic nervous system (noradrenergic vasoconstrictor nerves and cholinergic active vasodilator nerves) [65, 68, 71]. The exact relationship between sudomotor activity and vasodilation at these sites has yet not been determined. Although it is widely accepted that cholinergic sudomotor nerves innervate sweat glands, whether the sudomotor and vasodilator nerves are one and the same or separate nerves remains to be corroborated [69]. Emerging data supports the belief that 96


efferent signals innervating eccrine sweat glands resulting from both thermal and psychological stresses travel along common neural pathways [40]. Interestingly, limited data exist in support of myoepithelial cells in the secretory portion of the eccrine gland providing a contractile force to facilitate the movement of sweat from the gland lumen to the skin surface [72]. Although the pulsatile nature of eccrine sweat secretion is well established [73, 74], a role for myoepithelial cells in driving this contractile force and the pharmacology mediating the response remain to be determined. Axillary apocrine sweat glands are known to respond vigorously to emotive stimuli and are physiologically activated by adrenergic and cholinergic agonists [34, 35]. However, myoepithelial contraction of the apocrine glands is purely adrenergic in nature, indicating that the pathway for ‘forcing’ the preformed apocrine sweat out into the follicular infundibulum is mediated via an adrenergic peripheral mechanism [35]. This finding is further supported by the observation that axillary apocrine glands express β2- and β3-adrenoceptors [3]. The available data suggest that apocrine glands respond to psychological stress via a sympathetic peripheral β-adrenergic pathway [3].

Humoral Control of Psychological Sweating

Robertshaw [61] suggested that circulating catecholamines produce effects in two ways: first, by direct local stimulation of eccrine sweat secretion and, second, by indirectly inhibiting secretion by reducing sympathetic outflow to the glands. Evidence for this model is inconclusive. Some early studies reported occasionally observing suppression of sweat under high stress conditions [75]. Later studies reported a more consistent suppression of palmar sweat by epinephrine [76]. Contradictory evidence was reported in patients diagnosed with anxiety neuroses with increased concentrations of circulating catecholamines, who were shown to be more responsive than normal controls to local injections of the cholinomimetic carbachol and phenylephrine [77–79]. However, as the intradermal injection of Botox is highly effective at preventing sweating [80], circulating catecholamines on their own are not capable of eliciting the primary sweat response during periods of acute psychological stress [81], suggesting that the humoral factors play little or no role in the activation of eccrine sweat glands. Sex steroid hormone concentrations have been shown to increase in the initial phase of acute psychosocial stress, though there is Harker

Stressful event

Brain Perception of acute psychological stress

Central motor control mediated by the amygdala Cholinergic peripheral innervation

Fig. 3. Conceptual model of psychological

sweating and the associated cutaneous response. Perception of acute psychological stress elicits primarily cholinergic neural innervation of eccrine sweat glands and adrenergic peripheral activation of apocrine sweat glands. Generalised eccrine and localised apocrine sweating results in perceivable sweating from the palmar and plantar skin surfaces, face and axilla, with concomitant odour generation from the axilla. Particularly in social situations, this cascade of sweat secretions and self-perceived awareness of sweat and malodour sets up an escalating and self-sustaining cycle, in which increased anxiety can result in more sweating, which in turn leads to more anxiety.

Cutaneous response

Increased sweat

Face

Axilla

Hands

Feet

Cutaneous response Increased odour

no evidence to suggest that they are directly responsible for the innervation of eccrine or apocrine sweat glands [82]. However, as psychological sweating in the axilla is not apparent before puberty, a role for these hormones in ‘priming’ this site to respond to psychological stress appears likely [83]. Evidence for the humoral control of apocrine glands involving circulating catecholamines remains to be established, but most evidence supports the proposition that human apocrine glands are controlled by the sympathetic nervous system via peripheral mechanisms involving catecholamines [3]. There is no available evidence that the elevation of circulatory glucocorticoids released by the HPA axis in response to psychological stress directly modulates apocrine or eccrine gland activity.

Function

Evolved as a fleeing reaction in different mammals, psychological sweating is thought to be a primitive function that was important when hunting animals or fighting enemies [84]. Physiological amounts of sweat on the Psychological Sweating

Generalized eccrine sweating over the entire body surface but sweating more evident at specific locations

Adrenergic peripheral activation

Localised apocrine sweating Axilla

palms and soles can improve friction by controlling the humidity of the stratum corneum, leading to an improved grip [85]. The cognitive appraisal of the stressfulness of a particular situation varies between individuals and across gender. Such differences have been observed in many studies in the perception of the stressfulness of a particular situation and the behavioural response to a particular psychological stressor. Stroud et al. [86] reported greater responses in young women to a social rejection challenge than in young men, but larger responses in men to an achievement challenge. Taylor et al. [87] suggested an evolutionary adaptation in females to the predominantly male fight-or-flight response, where the female response might be more accurately referred to as ‘tend and befriend’, such that the female stress response is characterised by caring for offspring and joining social groups to reduce vulnerability [87]. Such results indicate that gender differences exist in the cognitive appraisal to particular stressors, leading to differential triggers of psychological sweating between males and females. One further consequence of psychological sweating, in particular relating to stress-induced axillary sweat, is the Skin Pharmacol Physiol 2013;26:92–100 DOI: 10.1159/000346930

97

release of chemosignals which serve a communicative function in signalling emotional states in human-to-human correspondence [88]. Axillary sweat collected from donors (senders) experiencing a particular stressor reduces perceptual acuity to happy facial expressions [89, 90], whilst the perceptual acuity to negative facial expressions is increased, i.e. fear and anger [91, 92], when presented to receivers under control conditions. Neutral or ambiguous facial expressions increased vigilance in receivers when simultaneously presented with axillary stress-induced sweat [93]. These reactions are not observed when receivers are presented with axillary sweat collected under emotionally neutral control conditions, i.e. non-stressed. These effects have been shown to occur outside conscious awareness and to induce specific neural and behavioural reactions in humans. Therefore, it is postulated that through psychological sweating in the axilla the experience of stress can be chemosensorily transmitted from the sender to the receiver [94].

diate eccrine sweat gland activity. Neuropeptides (VIPs) may play a role in psychological sweating in conjunction with cholinergic innervation by augmenting cAMP accumulation in the secretory cells. The level of skin sympathetic nerve activity at different body sites to regulate cutaneous arteriole blood flow may also influence the innervation of adjacent sweat glands, leading to an increased role for adrenergic innervation of sweat glands in these regions. The amygdala appears to be the major brain centre mediating sweat gland activity in response to acute psychological stress. Apocrine sweating is strongly regulated by psychological stimuli and is mediated via an adrenergic peripheral pathway, with secretory activity highly localised to those skin sites hosting apocrine glands. The role of the axilla in psychological sweating, due to the location of both eccrine and apocrine glands resulting in the formation of malodour and visible sweat production, can be problematic; such that acute psychological sweating in the axilla can lead to social embarrassment that can ultimately erode self-confidence and reduce the quality of life.

Conclusions

Psychological sweating in response to emotive stimuli like stress, anxiety, fear and pain can occur over the whole body surface but is most evident on the palms, soles, face and axilla (fig. 3). Cholinergic innervation is the primary effector eliciting activation of the eccrine sweat glands; however, a dual innervation pathway for these glands (adrenergic and cholinergic) may augment some small increase in sweat output during psychological stress events. Although, adrenergic innervation of eccrine sweat glands in the absence of any cholinergic stimulation elicits only a weak response in terms of stimulating gland activity. Circulating catecholamines do not appear to directly me-

Acknowledgements The author thanks Prof. Douglas Bovell, Glasgow Caledonian University, for permission to use the histological sections shown in figures 1 and 2. The author also thanks Clive Harding for a critical review of the manuscript.

Disclosure Statement None declared. Mark Harker was an employee of Unilever Research & Development during the preparation of this manuscript. The funder played no direct role in the preparation of this manuscript.

References 1 Chalmers TM, Keele CA: The nervous and chemical control of sweating. Br J Dermatol 1952;64:43–54. 2 Allen JA, Armstrong JE, Roddie IC: The regional distribution of psychological sweating in man. J Physiol 1973;235:749–759. 3 Lindsay SL, Holmes S, Corbett AD, Harker M, Bovell DL: Innervation and receptor profiles of the human apocrine (epitrichial) sweat gland: routes for intervention in bromhidrosis. Br J Dermatol 2008;159:653–660. 4 Martin A, Hellhammer J, Hero T, Max H, Terstegen L, Natsch A: Effective prevention of stress-induced sweating and axillary mal-

98

odour formation in teenagers. Int J Cos Sci 2011;33:90–97. 5 Sato K, Kang WH, Saga K, Sato KT: Biology of sweat glands and their disorders. I. Normal sweat gland function. J Am Acad Dermatol 1989;20:537–563. 6 Quinton PM, Elder HY, McEwan Jenkinson D, Bovell, DL: Structure and function of human sweat glands; in Laden K, Felger CB (eds): Antiperspirants and Deodorants. New York, Marcel Dekker, 1999, pp 17–57. 7 Wilke K, Martin A, Terstegen L, Biel SS: A short history of sweat gland biology. Int J Cos Sci 2007;29:169–179.


8 Bovell DL, Corbett, AD, Holmes S, MacDonald A, Harker M: The absence of apoeccrine glands in the human axilla has disease pathogenetic implications, including axillary hyperhidrosis. Brit J Dermatol 2007; 156: 1278– 1286. 9 Goldsmith LA: Biology of eccrine and apocrine sweat glands; in Fitzpatrick TB (ed): Dermatology in General Medicine. New York, McGraw-Hill, 1998, pp 155–164. 10 Hwang K, Baik SH: Distribution of hairs and sweat glands on the bodies of Korean adults: a morphometric study. Acta Anat 1997; 158: 112–120.

Harker

11 Szabó G: The regional anatomy of the human integument with special reference to the distribution of hair follicles, sweat glands and melanocytes. Phil Trans R Soc Lond B 1967; 252:447–485. 12 Sato K, Leidal R, Sato F: Morphology and development of an apoeccrine sweat gland in human axillae. Am J Physiol 1987;252:R166– R180. 13 Sato K, Sato F: Defective beta-adrenergic response of cystic fibrosis sweat glands in vivo and in vitro. J Clin Invest 1984;73:1763–1771. 14 Uno H: Sympathetic innervation of the sweat glands and piloerector muscle of macaques and human beings. J Invest Dermatol 1977; 69:112–130. 15 Randall WC, Kimura KK: The pharmacology of sweating. Pharma Rev 1955;7:365–397. 16 Coon JM, Rothman S: The sweat response to drugs with nicotine-like action. J Pharmacol Exp Ther 1941;73:1–11. 17 Connolly M, de Berker D: Management of primary hyperhidrosis. Am J Clin Dermatol 2003;4:681–697. 18 Wada M: Sudorific action of adrenaline on the human sweat glands and determination of their excitability. Science 1950;111:376–377. 19 Foster KG, Weiner JS: Effects of cholinergic and adrenergic blocking agents on the activity of the eccrine sweat glands. J Physiol (Lond) 1970;210:883–895. 20 Foster KG, Ginsberg J, Weiner JS: Role of circulating catecholamines in human eccrine sweat gland control. Clin Sci 1970; 39: 823– 832. 21 Sato K, Sato F: Pharmacological responsiveness of isolated single eccrine sweat glands. Am J Physiol 1981;240:R44–R51. 22 Sato K: Update on pharmacology of the eccrine sweat gland. Trends Pharmacol Sci 1984;5:391–393. 23 Low PA, Opfer-Gehrking TL, Kihara M: In vivo studies on receptor pharmacology of the human eccrine sweat gland. Clin Aut Res 1992;2:29–34. 24 Riedl B, Nischik M, Birklein F, Neudorfer B, Handwerker HO: Spatial extension of sudomotor axon reflex sweating in human skin. J Auton Nerv Sys 1998;69:83–88. 25 Sato K, Sato F: Effect of VIP on sweat secretion and cAMP accumulation in isolated simian eccrine glands. Am J Physiol 1987; 253:R935–R941. 26 Bovell DL, Santic R, Kofler B, Hermann A, Wilson D, Corbett A, Lang R: Activation of chloride secretion via proteinase-activated receptor 2 in a human eccrine sweat gland cell line – NCL-SG3. Exp Dermatol 2008;17:505– 511. 27 Schlereth T, Dittmar JO, Seewald B, Hamm H: Peripheral amplification of sweating – a role for calcitonin gene-related peptide. J Physiol (Lond) 2006;576:823–832. 28 Holub B, Brodowicz B, Bovell DL, Kofler B, Lang R: Galanin and its receptors as modulators of eccrine sweat gland physiology. Exp Dermatol 2012;21:e17–e18.

Psychological Sweating

29 Bovell DL, Lindsay SL, Holdsworth RJ: P2Y1, P2Y2, and P2Y4 receptor localisation in human hyperhidrotic eccrine sweat glands. Br J Surg 2003;90:1–6. 30 Kumazawa K, Sobue G, Mitsuma T, Ogawa T: Modulatory effects of calcitonin gene-related peptide and substance P on human cholinergic sweat secretion. Clin Auton Res 1994; 4: 319–322. 31 Berg TJ, Levy DM, Reid G, Abraham RR: The effects of vasoactive intestinal polypeptide and substance P on methacholine-induced sweating and vascular flare in diabetic neuropathy. Clin Auton Res 1995;5:159–164. 32 Aoki T: Stimulation of human axillary apocrine sweat glands by cholinergic agents. J Invest Dermatol 1962;38:41–44. 33 Shelley WB, Hurley HJ: The physiology of the human axillary apocrine sweat gland. J Invest Dermatol 1953;20:285–297. 34 Sato K, Sato F: Sweat secretion by human axillary apoeccrine sweat gland in vitro. Am J Physiol 1987;252:R181–R187. 35 Sato K: Pharmacological responsiveness of the isolated human axillary apocrine gland. Br J Dermatol 1980;103:235–243. 36 Cacioppo JT, Berntson GG, Malarkey WB, Kiecolt-Glaser JK, Sheridan JF, Poehlmann, KM, Burleson, MH, Ernst JM, Hawkley LC, Glaser R: Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis. Ann NY Acad Sci 1998; 840:664–673. 37 Herman JP, Ulrich-Lai YM: Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009;10:397–409. 38 Ryan KK, Grayson BE, Jones KR, Schneider AL, Woods SC, Seeley RJ, Herman JP, UlrichLai YM: Physiological responses to acute psychological stress are reduced by the PPARγ agonist rosiglitazone. Endocrinol 2012; 153: 1279–1287. 39 Black PH: Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 2002;16:622–653. 40 Machado-Moreira CA, Taylor NAS: Psychological sweating from glabrous and nonglabrous skin surfaces under thermoneutral conditions. Psychophysiology 2011;49:369–374. 41 Storm H: Development of emotional sweating in preterms measured by skin conductance changes. Early Hum Dev 2001;62:149–158. 42 Swaile DF, Elstun LT, Benzing KW: Clinical studies of sweat rate reduction by an over-thecounter soft-solid antiperspirant and comparison with a prescription antiperspirant product in male panellists. Br J Dermatol 2012;166(suppl 1):22–26. 43 Boucsein W: Electrodermal Activity. New York, Plenum Press, 1992. 44 Le Doux, J: The Psychological Brain. New York, Simon & Schuster, 1996. 45 Kling A, Brothers L: The amygdala and social behavior; in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction. New York, Wiley-Liss, 1992.

46 Bohus B, Koolhaas JM, Luiten PGM, Luiten PGM, Korte SM, Roozendaal B, Wiersma A: The neurobiology of the central nucleus of the amygdala in relation to neuroendocrine and autonomic outflow. Prog Brain Res 1996;107: 447–460. 47 Bagshaw MH, Kimble DP, Pribram KH: The GSR of monkeys during operating and habitation and after ablation of the amygdala hippocampus and inferotemporal cortex. Neuropsychologia 1965;3:111–119. 48 Lee GP, Arena JG, Meador KJ, Smith JR, Loring DW, Flanigin HF: Change in autonomic responsiveness following bilateral amygdalotomy in humans. Neuropsychiatry Neuropsychol Behav Neurol 1988;1:119–129. 49 Asahina M, Suzuki A, Mori M, Kanesaka T, Hattori T: Emotional sweating response in a patient with bilateral amygdala damage. Int J Psychophysiol 2003;47:87–93. 50 Asahina M, Fujinuma Y, Yamanaka Y, Fukushima T, Katagiri A, Ito S, Kuwabara S: Diminished psychological sweating in patients with limbic encephalitis. J Neurol Sci 2011; 306:16–19. 51 Mangina CA, Beuzeron-Mangina JH: Direct electrical stimulation of specific human brain structures and bilateral electrodermal activity. Int J Psychophysiol 1996;22:1–8. 52 Homma S, Nakajima Y, Toma, S, Ito T, Shibata T: Intracerebral source localization of mental process-related potentials elicited prior to mental sweating response in humans. Neurosci Lett 1998;247:25–28. 53 Champion RH: Sweat glands; in Champion RH, Gillman T, Rook AJ, Sims RT (eds): An Introduction to the Biology of the Skin. Philadelphia, Davis, 1970, pp 175–183. 54 Kennard DW: The nervous regulation of the sweating apparatus of the human skin, and emotive sweating in thermal sweating areas. J Physiol 1963;165:457–467. 55 Machado-Moreira CC, Taylor NA: Sudomotor responses from glabrous and non-glabrous skin during cognitive and painful stimulations following passive heating. Acta Physiol 2012;204:571–581. 56 Machado-Moreira CC, McLennan PL, Lillioja S, van Dijk W, Caldwell JN, Taylor NA: The cholinergic blockade of both thermally and non-thermally induced human eccrine sweating. Exp Physiol 2012;97:930–942. 57 Smith CJ, Havenith G: Body mapping of sweating patterns in male athletes in mild exercise-induced hyperthermia. Eur J Appl Physiol 2011;111:1391–1404. 58 Ganong WF: Review of Medical Physiology, ed 11. Los Altos, Lange Medical Publications, 1983. 59 Jensen D: The Human Nervous System. New York, Appleton-Century-Crofts, 1980. 60 Guyton AC: Basic Human Neurophysiology, ed 3. Philadelphia, Saunders, 1981. 61 Robertshaw D: Neuroendocrine control of sweat glands. J Invest Dermatol 1977;69:121– 129.


99

62 Noback CR, Demarest RJ: The Nervous System: Introduction and Review. New York, McGraw Hill, 1972. 63 Edelberg R: Electrical activity of the skin: its measurement and uses in psychophysiology; in Greenfield J, Sternbach RA (eds): Hand Book of Psychophysiology. New York, Holt, Rhinehart & Winston, 1972, pp 367–418. 64 Lader MH, Montagu JD: The psycho-galvanic reflex: a pharmacological study of the peripheral mechanism. J Neurol Neurosurg Psych 1962;25:126–133. 65 Rowell LB: Reflex control of the cutaneous vasculature. J Invest Dermatol 1977; 69: 154– 166. 66 Johnson JM: Nonthermoregulatory control of human skin blood flow. J Appl Physiol 1986; 61:1613–1622. 67 Johnson JM, Brengelmann GL, Hales JR, Vanhoutte PM, Wenger CB: Regulation of the cutaneous circulation. Fed Proc 1986; 45: 2841–2850. 68 Johnson JM, Proppe DW: Cardiovascular adjustments to heat stress; in Fregly MJ, Blatteis CM (eds): Handbook of Physiology. Oxford, Oxford University Press, 1996, pp 215–243. 69 Kellogg DL: A physiological systems approach to human and mammalian thermoregulation: in vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans during thermoregulatory challenges. J Appl Physiol 2006;100:1709–1718. 70 Johnson JM, Duane W, Proppe DW: Cardiovascular Adjustments to Heat Stress. Compr Physiol 2011(suppl 14):215–243. 71 Charkoudian N, Johnson JM: Reflex control of cutaneous vasoconstrictor system is reset by exogenous female reproductive hormones. J Appl Physiol 1999;87:381–385. 72 Kurzen H, Schallreuter KU: Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors. Exp Dermatol 2004;13(suppl 4):27–30. 73 Kamijo YI, Lee K, Mack GW: Active cutaneous vasodilation in resting humans during mild heat stress. J Appl Physiol 2005;98:829– 837.

100

74 Sugenoya J, Ogawa T, Jmai K, Ohnishi N, Natsume K: Cutaneous vasodilation responses synchronize with sweat expulsions. Eur J Appl Physiol 1995;71:33–40. 75 Darrow CW: Neural mechanisms controlling the palmar galvanic skin reflex and palmar sweating. Arch Neurol Psychiatry 1937; 37: 641–663. 76 Harrison J, MacKinnon PC: Physiological role of the adrenal medulla in the palmar anhidrotic response to stress. J Appl Physiol 1966;21:88–92. 77 Maple S, Bradshaw CM, Szabadi E: Pharmacological responsiveness of sweat gland in anxious patients and healthy volunteers. Br J Psychiatry 1982;141:154–161. 78 Van den Brock MD, Bradshaw CM, Szabadi E: The effects of a psychological ‘stressor’ and a raised ambient temperature on the pharmacological responsiveness of human eccrine sweat glands: implications for sweat gland hyper-responsiveness in anxiety states. Eur J Clin Pharmacol 1984;26:209–213. 79 Buceta JM, Bradshaw CM, Szabadi E: Hyperresponsiveness of eccrine sweat glands to carbachol in anxiety neurosis: comparison of male and female patients. Br J Clin Pharmacol 1985;19:817–822. 80 Lowe N, Campanati A, Bodokh I, Cliff S, Jaen P, Kreyden O, Naumann M, Offidani A, Vadoud J, Hamm H: The place of botulinum toxin type A in the treatment of focal hyperhidrosis. Br J Dermatol 2004;151:1115–1122. 81 Glaser DA, Loss R, Beddingfield F, Coleman W: Four-year longitudinal data on the efficacy and safety of repeated botulinum toxin type A therapy for primary axillary hyperhidrosis. J Am Acad Dermatol 2007; 56:AB61– AB61. 82 Lennartsson A-K, Kushnir MM, Bergquist J, Billig H, Jonsdottir IH: Sex steroid levels temporarily increase in response to acute psychosocial stress in healthy men and women. Int J Psychophysiol 2012;84:246–253. 83 Seoung S, Kim BS: Hyperhidrosis as the only manifestation of hyperandrogenism in an adolescent girl. Arch Dermatol 2000; 136: 430– 431.


84 Holzle E: Pathophysiology of sweating. Curr Probl Dermatol 2002;30:10–22. 85 Adelman S, Taylor CR, Heglund NC: Sweating on paws and palms: what is its function? Am J Physiol 1975;229:1400–1402. 86 Stroud LR, Salovey P, Epel ES: Sex differences in stress responses: social rejection versus achievement stress. Biol Psych 2002; 52: 318– 327. 87 Taylor SE, Klein LC, Lewis BP, Gruenewald TL, Gurung RA, Updegraff JA: Biobehavioural responses to stress in females: tendand-befriend, not fight-or-flight. Psychol Rev 2000;107:411–429. 88 De Groot JH, Smeets MA, Kaldewaij A, Duijndam MJ, Semin GR: Chemosignals communicate human emotions. Psychol Sci 2012;23:1417–1424. 89 Pause BM, Ohrt A, Prehn A, Ferstl R: Positive emotional priming of facial affect perception in females is diminished by chemosensory anxiety signals. Chem Senses 2004; 29: 797– 805. 90 Zernecke R, Haegler K, Kleemann AM, Albrecht J, Frank T, Linn J, Brückmann H, Wiesmann M: Effects of male anxiety chemosignals on the evaluation of happy facial expressions. J Psychophysiol 2001; 25: 116– 123. 91 Zhou W, Chen D: Fear-related chemosignals modulate recognition of fear in ambiguous facial expressions. Psychol Sci 2009; 20: 177– 183. 92 Mujica-Parodi LR, Strey HH, Frederick B, Savoy R, Cox D, Botanov Y, Tolkunov D, Rubin D, Weber J: Chemosensory cues to conspecific emotional stress activate amygdala in humans. PLoS One 2009;4:e6415. 93 Rubin D, Botanov Y, Hajcak G, Mujica-Parodi LR: Second-hand stress: inhalation of stress sweat enhances neural response to neutral faces. Soc Cogn Affect Neurosci 2012; 7: 208– 212. 94 Pause BM: Processing of body odor signals by the human brain. Chemosens Percept 2012:5; 55–63.

Harker