Chapter 83. Biology of Eccrine and Apocrine Glands

In humans, sweat glands generally are found as two types, (1) eccrine and (2) apocrine. Eccrine-gland sweat allows the body to control its internal temperature in response to thermal stress. Apocrine gland function is more obscure but likely includes pheromone production.

Humans have approximately 2–4 million sweat glands.1 Sweat glands are found over nearly the entire body surface, and are especially dense on the palms, soles, forehead, and upper limbs.2 Analgen of eccrine sweat glands first appear in the 3.5-month-old fetus on the palms and soles (see Chapter 7), then develop in the axillary skin in the fifth fetal month, and finally develop over the entire body by the sixth fetal month.3 The analog of the eccrine sweat gland, which developed from the epidermal ridge, is double layered, and develops a lumen between the layers between the fourth and eighth fetal months. By the eighth fetal month eccrine secretory cells resemble those of the adult; by the ninth fetal month myoepithelial cells form.

Two distinct segments, the secretory coil and the duct, form the eccrine sweat gland. The secretory coil secretes an isotonic sweat, while the duct resorbs Na+ and Cl−, thus producing sweat to cool the body while preserving Na+ and Cl– body stores.

The secretory coil contains three distinct cell types: (1) clear (secretory), (2) dark (mucoid), and (3) myoepithelial.4 The clear and dark cells occur in approximately equal numbers but differ in their distribution (Fig. 83-1). While the dark cells border the apical (luminal) surfaces, the clear cells rest either directly on the basement membrane or on the on the myoepithelial cells. The clear cells directly access the lumen by forming intercellular canaliculi (Fig. 83-2). Spindle shaped contractile myoepithelial cells lie on the basement membrane and abut the clear cells. The adult secretory coil is approximately 2–5-mm long, and approximately 30–50 μm in diameter. Heat accumulation results in larger sweat glands and ducts, and their dimensions, in turn, correlate with enhanced sweat output.5 Clear cells contain abundant mitochondria and an autofluorescent body, called the lipofuscin granule, in the cytoplasm. The clear cell plasma membrane forms many villi. The clear cell secretes water and electrolytes. Dark cells have a smooth cell surface and contain abundant dark cell granules.4 The function of dark cells are unknown. Myoepithelial cells contain actin filaments6 and are contractile,7,8 producing pulsatile sweat.

The eccrine sweat duct consists of an outer ring of peripheral or basal cells and an inner ring of luminal or cuticular cells. It seems that the proximal (coiled) duct is functionally more active than the distal straight portion in pumping Na+ for ductal Na+ reabsorption, because Na+, K+-adenosine triphosphatase (ATPase) activity and the number of mitochondria are higher in the proximal portion (Fig. 83-3).4,7,9,10 In contrast, the luminal ductal cells have fewer mitochondria, much less Na+, K+-ATPase activity, and a dense layer of tonofilaments near the luminal membrane, which is often referred to as the cuticular border. The cuticular border provides structural resilience to the ductal lumen, which may dilate whenever ductal flow of sweat is blocked. The entire structural organization of the duct is well designed for the most efficient Na+ absorptive function. The luminal membrane serves as the absorptive surface by accommodating both Na+ and Cl− channels, and the basal ductal cells serve in Na+ pumping by providing maximally expanded Na+ pump sites and efficient energy metabolism. The lumen and the duct contain β-defensin, an antimicrobial, cysteine-rich, low-molecular-weight peptide.11,12 In the epidermis, the duct spirals tightly upon itself.

Neural Control of Eccrine Sweating

The preoptic hypothalamic area plays an essential role in regulating body temperature: local heating of the preoptic hypothalamic tissue activates generalized sweating, vasodilatation, and rapid breathing, whereas local cooling of the preoptic area causes generalized vasoconstriction and shivering. The elevation of hypothalamic temperature associated with an increase in body temperature provides the strongest stimulus for thermoregulatory sweating responses, while cutaneous temperature exerts a weaker influence on the rate of sweating.13 On a degree-to-degree basis, an increase in internal temperature is about nine times more efficient than an increase in mean skin temperature in stimulating the sweat center. The local temperature effect is speculated to be due to increased release of periglandular neurotransmitters.

The sweating in menopausal “hot flashes” reinforces the concept of a central hypothalamic mechanism for thermal sweating, but also shows that the response of individuals to the same changes in core temperature can vary. Although hormonal factors influence sweating during menopause, excessive sweating does not correlate simply with hormonal levels. Instead, menopausal hot flashes seem to be due to a hypersensitive brain response (particularly the hypothalamus, but perhaps the insula, anterior cingulate, amygdala, and primary somatosensory cortex as well). In asymptomatic menopausal women and premenopausal women, the core temperature can change up to 0.4°C (33°F) without eliciting a response. In symptomatic postmenopausal women, changes as small as 0.1°C (32°F) trigger peripheral vasodilation and sweating. Why the brain is hypersensitive to small changes in core temperature is poorly understood, but increased levels of brain norepinephrine appear to influence the response to small changes in core temperature through their action on α2-adrenergic receptors in the brain; higher levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol have also been found in symptomatic menopausal women than in asymptomatic women. Decreased norepinephrine release is postulated as the mechanism by which clonidine relieves hot flashes in symptomatic women. Decreased core temperature may be the reason that women with decreased body mass index tend to have fewer symptoms, even though their estrogen levels probably are lower than those in women with increased body mass index. Levels of estrogen, luteinizing hormone, and β-endorphins also were originally thought to influence hot flashes, but later studies have suggested no association.14

Innervation

Efferent nerve fibers originating from the hypothalamic preoptic sweat center descend through the ipsilateral brainstem and medulla and synapse in the intermediolateral cell columns of the spinal cord without crossing (although sympathetic vasomotor fibers may partially cross).15 The myelinated axons rising from the intermediolateral horn of the spinal cord (preganglionic fibers) pass out in the anterior roots to reach (through white ramus communicans) the sympathetic chain and synapse. Unmyelinated postganglionic sympathetic class C fibers arising from sympathetic ganglia join the major peripheral nerves and end around the sweat gland. The supply to the skin of the upper limb is commonly from T2 to T8. The face and the eyelids are supplied by T1 to T4, so that resection of T2 for the treatment of palmar hyperhidrosis is likely to cause Horner syndrome. The trunk is supplied by T4 to T12 and the lower limbs by T10 to L2. Unlike the sensory innervation, a significant overlap of innervation occurs in the sympathetic dermatome because a single preganglionic fiber can synapse with several postganglionic fibers.

The major neurotransmitter released from the periglandular nerve endings is acetylcholine (Ach), an exception to the general rule of sympathetic innervation, in which noradrenaline is the peripheral neurotransmitter. In addition to ACh, adenosine triphosphate (ATP), catecholamine, vasoactive intestinal peptide, atrial natriuretic peptide, calcitonin gene-related peptide, and galanin have been localized in the periglandular nerves. The significance of these peptides or neurotransmitters in relation to sweat gland function is not fully understood.

Botulinum toxin interferes with ACh release. Its heavy chain binds the neurotoxin selectively to the cholinergic terminal and the light chain acts within the cells to prevent ACh release. Type A toxin cleaves sensory nerve action potential-25, a 25-kDa synaptosomal-associated protein; the type B light chain cleaves vesicle-associated membrane protein (also called synaptobrevin). Botulinum toxins are used for symptomatic relief of hyperhidrosis.16 A more detailed description can be found in Chapters 84 and 255.

Denervation

In humans, the sweating response to intradermal injection of nicotine or ACh disappears within a few weeks after denervation of the postganglionic fibers,17 while the sweating response to heat ceases immediately after resection of the nerves. In contrast, after denervation of preganglionic fibers (due to spinal cord injuries or neuropathies), pharmacologic responsiveness of the sweat glands is maintained from several months to 2 years, even though their thermally induced sweating is no longer present.18

Emotional Sweating

Sweating induced by emotional stress (emotional sweating) can occur over the whole skin surface in some individuals, but it is usually confined to the palms, soles, axillae, and the forehead. Emotional sweating on the palms and soles ceases during sleep, whereas thermal sweating occurs even during sleep if the body temperature rises. Because both types of sweating can be inhibited by atropine, emotional sweating is cholinergically medicated.

Pharmacology of the Eccrine Sweat Gland and Sweating Rate

Sweat glands respond to cholinergic agents, α- and β-adrenergic stimulants, and other periglandular neurotransmitters, such as vasoactive intestinal peptide and ATP. Periglandular ACh is the major stimulant of sweat secretion, and its periglandular concentration determines the sweat rate in humans. When dissociated clear cells are stimulated in vitro by cholinergic agents, they lose K+ & Cl−, increase intracellular Ca2+, and shrink, mimicking actions seen in vivo.19 Striking individual differences exist in the degree of sweating in response to a given thermal or physical stress. In general, males perspire more profusely than females.20 The sweat rate in a given area of the skin is determined by the number of active glands and the average sweat rate per gland. The maximal sweat rate per gland varies from 2 to 20 nL/min2. Sweat rate increases during acclimatization, but the morphologic and pharmacologic bases of the individual and regional differences in sweating rate during acclimatization are still poorly understood (Fig. 83-4). In thermally induced sweating, the sweat rate can be mathematically related to the body and skin temperatures in a given subject only in the low sweat rate range. Cholinergic stimulation yields a five to ten times higher sweating rate than does β-adrenergic stimulation. α-Adrenergic stimulation (by phenylephrine) is no more potent than isoproterenol (ISO) (a β-adrenergic agonist) in humans in vivo.21 Whereas cholinergic sweating begins immediately on intradermal injection, β-adrenergic sweating requires a latent period of from 1 to 2 minutes, which suggests that the intracellular mechanism of sweat induction may be different for methacholine and for ISO. Because the sweat rate in response to adrenergic agents is rather low, it may be reasonable to surmise that adrenergic stimulation in periglandular nerves may be involved in the regulation of sweat gland function but not in the induction of sweat secretion. One consequence of dual cholinergic and adrenergic innervation is to maximize tissue accumulation of cyclic adenosine monophosphate, which may be instrumental in stimulating the synthesis of sweat and glandular hypertrophy of the sweat gland. The possibility that periglandular catecholamine is directly involved in emotional sweating or sweating associated with pheochromocytoma22 may be ruled out, because these sweating responses can be blocked by anticholinergic agents.

Pharmacology and Function of Eccrine Myoepithelium

The periodicity of sweat secretion in vivo is caused by the periodicity of central nerve impulse discharges, which occur synchronously with vasomotor tonus waves. Myoepithelial contraction occurs with cholinergic stimulation, but neither α- nor β-adrenergic agents induce tubular contraction.23 While the myoepithelium may contribute to sweat production via pulsatile contractions, it also seems to provide structural support for the secretory epithelium, especially under conditions in which stagnation of sweat flow (due to ductal blockade) results in an increase in luminal hydrostatic pressure.8

Energy Metabolism

Sweat secretion is mediated by the energy (i.e., ATP)-dependent active transport of ions, so a continuous supply of metabolic energy is mandatory for sustained sweat secretion. Endogenous glycogen stored in the clear cells can sustain sweat secretion for less than 10 minutes; thus the sweat gland must depend almost exclusively on exogenous substrates for its energy metabolism. Mannose, lactate, and pyruvate are used nearly as readily as glucose; other hexoses, fatty acids, ketone bodies, intermediates of the tricarboxylic acid cycle, and amino acids are either very poorly used or not used as substrates. The physiologic significance of lactate or pyruvate utilization by the sweat gland is not yet clear. However, because the plasma level of glucose (5.5 mM) is much higher than that of lactate (1–2 mM) or pyruvate (less than 1 mM), glucose may play a major role in sweat secretion. Oxidative metabolism of glucose is favored as the major route of ATP formation for secretory activity.23

Composition of Human Eccrine Sweat

Inorganic Ions

Sweat is formed in two steps: (1) secretion of a primary fluid containing nearly isotonic NaCl concentrations by the secretory coil, and (2) reabsorption of NaCl from the primary fluid by the duct. Although a number of factors affect ductal NaCl absorption, the sweat rate (and thus the transit time of sweat) has the most important influence on final NaCl concentration. Sweat NaCl concentration increases with increasing sweat rate to plateau at around 100 mM (Fig. 83-5). Potassium (K+) concentration in sweat is relatively constant. It ranges from 5 to 10 mM, which is slightly higher than plasma K+ concentration. HCO3− concentration in the primary sweat fluid is approximately 10 mM, but that of final sweat is less than 1 mM, which indicates that HCO3− is reabsorbed by the duct, presumably accompanied by ductal acidification.24 Sweat NaCl concentration is increased in individuals with cystic fibrosis. Aquagenic wrinkling of the palms (whitened, wrinkling, and papillation of the palms after brief water exposure) is seen more frequently in carriers and patients with cystic fibrosis (see Chapter 84).

Lactate

The concentration of lactate in sweat usually depends on the sweat rate. At low sweat rates, lactate concentration is as high as 30–40 mM, but it rapidly drops to a plateau at around 10–15 mM as the sweat rate increases. Acclimatization is known to lower sweat lactate concentrations, whereas arterial occlusion rapidly raises sweat NaCl and lactate concentrations and reduces the sweat rate.23 Sweat lactate is probably produced by glycolysis of glucose by the secretory cells.25

Urea

Urea in sweat is derived mostly from serum urea.26 Sweat urea content is usually expressed as a sweat–plasma ratio (S/P urea). S/P urea is high (2–4) at a low sweat rate range but approaches a plateau at 1.2–1.5 as the sweat rate increases.

Ammonia and Amino Acids

Ammonia concentration in sweat is 0.5–8 mM,27 which is 20–50 times higher than the plasma ammonia level. The concentration of sweat ammonia is inversely related to the sweat rate and sweat pH. Free amino acids are present in human sweat,27 although it is not clear what proportion of measured amino acids derive from epidermal contamination.

Proteins Including Proteases

The concentration of sweat protein in the least contaminated, thermally induced sweat is approximately 20 mg/dL, with the major portion being low-molecular-weight proteins (i.e., MW <10,000). Because sweat samples collected by simple scraping, and even those collected with a plastic bag, can be massively contaminated with plasma or epidermal proteins, previous reports on the presence of α- and γ-globulins, transferrin, ceruloplasmin, orosomucoid, and albumin28,29 and immunoglobulin E must be carefully reexamined. The sweat samples collected over an oil barrier placed on the skin (the least-contaminated sweat) contain no or trace of γ-globulin and a very small amount of albumin. Yokozeki et al30 also reported the presence of cysteine proteinases and their endogenous inhibitors in sweat and the sweat gland. Dermcidin is an antimicrobial peptide produced and secreted in sweat.31 Other organic compounds reported to be present in sweat include histamine,32 prostaglandin,33 and vitamin K-like substances.34 Sweat also contains traces of pyruvate and glucose. Sweat glucose increases concurrently with a rise in plasma glucose level. Some orally ingested drugs, including griseofulvin,35 ketoconazole,36 amphetamines,37 and various chemotherapeutic agents,38 are secreted in sweat.

Mechanisms of Sweat Secretion

Several distinct sequential processes lead to eccrine gland sweat production39: (1) stimulation of the eccrine sweat gland by ACh via increased intra cellular Ca2+; (2) Ca2+-stimulated loss of cellular K+, Cl−, and H2O, which leads to eccrine gland cell shrinkage; and (3) volume-activated transcellular plus paracellular fluxes of Na+, Cl−, and H2O, which leads to net flux of largely isotonic NaCl solution into the glandular lumen. These processes are illustrated in Fig. 83-6.

Sweating initially is stimulated when ACh is released from periglandular cholinergic nerve endings in response to thermal or emotional stimuli. ACh binds to cholinergic receptors on the clear cell plasma membrane, stimulating intracellular Ca2+ release and influx, and increasing cytosolic Ca2+ concentrations. Increased intracellular Ca2+, in turn, opens Ca2+-sensitive Cl− and K+ channels in the clear cell basolateral membrane, which allows Cl− and K+ to escape. Because H2O follows K+ and Cl−, to maintain cell iso-osmolarity, the cell shrinks.39,40

This decrease in cell volume sets off a second cascade of cell signaling events. First, decreased cell volume stimulates the NKCC141 class of Na/K/2Cl cotransporters, which carry Na+, K+, and 2Cl− into the cell in an electrically neutral fashion (i.e., two cations and two anions cancel out net charges). The resulting increase in cytosolic Na+ activates the Na+, K+-ATPase, located in the basolateral membrane, which recycles Na+ and K+ across the basolateral membrane. The net movement of the negatively charged Cl− ion across the apical membrane into the lumen in turn drives the positively charged Na+ ion into the lumen as well, along a paracellular pathway. Therefore, the final product of glandular secretion is the net movement of Na+, Cl−, and H2O into the glandular lumen to form the isotonic NaCl precursor of sweat.

ACh-induced sweating, which constitutes the bulk of sweat production, appears to be mediated by intracellular Ca2+, as detailed earlier. In contrast, adrenergic-induced sweating appears to be mediated by increased intracellular cyclic adenosine monophosphate.41

Mechanism of Ductal Reabsorption

Because the production of large sweat volumes could lead to dangerous losses of NaCl, the sweat duct has evolved to reabsorb NaCl, which minimizes electrolyte loss, even at high sweat volumes (Fig. 83-7).

Ductal Na+ reabsorption is accomplished through the coordinated activities of intracellular enzymes and plasma membrane ion channels, pumps, and exchangers. These mechanisms not only reabsorb electrolytes but also acidify the sweat, which results in a final sweat product that is hypotonic and acidic. Na+ reenters the duct cells through the apical membrane via amiloride-sensitive42 epithelial Na+ channels (ENaC)42 and is transported across the basolateral membrane by ouabain-sensitive10 Na+, K+-ATPase pumps. Cl− transport appears to be both transcellular and paracellular, with the cystic fibrosis transmembrane regulator (CFTR) Cl− channels playing an important role in transcellular fluxes.43 In cystic fibrosis, CFTR Cl− channels are mutated, and eccrine duct Cl− reabsorption is defective, although not completely abolished.24 Na+ is increased in the duct and the sweat at the skin surface.44 Unlike in the lung, CFTR mutations do not lead to increased ENaC-mediated Na+ influx, which suggests that the CFTR–ENaC interactions seen in other tissues differ from that in the eccrine duct. Sweat acidification appears to be mediated via the enzyme carbonic anhydrase, the HCO3−/Cl and Na+/H+ exchangers, and the V-type H+ ATPase. The intracellular enzyme carbonic anhydrase catalyzes HCO3− and H+ production. Intracellular HCO3− is cleared via the HCO3−/Cl antiporter, whereas H+ is pumped into the luminal sweat by the V-type H+ ATPase.45 The Na+/H+ antiporter NHE1 (Na+/H+ exchanger isoform 1)44,46 found in the basolateral membrane, is important in intracellular pH regulation.

Several drugs are known to modify ductal NaCl reabsorption. When aldosterone is injected systemically or locally, the Na/K ratio in sweat begins to decrease within 6 hours, reaching a nadir at 24 hours and returning to the preinjection level in 48–72 hours.44 Na+ deprivation stimulates both renin and aldosterone secretion, but high thermal stress per se [a single 1-hour exposure of humans to a temperature of 40°C (104°F)] is a potent stimulator of renin and aldosterone secretion in either the presence or absence of sodium deprivation. In an in vitro sweat gland preparation, neither acetazolamide (a carbonic anhydrase inhibitor) nor antidiuretic hormone changed ductal or secretory function. However, more potent carbonic anhydrase inhibitors, such as topiramate,47 have been reported to induce oligohidrosis.

In addition to the eccrine sweat glands, described earlier, apocrine sweat glands are found in humans, largely confined to the regions of the axillae and perineum.48 They do not become functional until just before puberty; thus, it is assumed that their development is associated with the hormonal changes at puberty, although the exact hormones have not been identified.

Anatomy

Apocrine glands are coiled and localized in the subcutaneous fat near the dermis. The gland consists of a single layer of cuboidal or columnar cells. These secretory cells rest on a layer of myoepithelial cells.49 The duct is composed of a double layer of cuboidal cells, and empties into hair follicle infundibulum.

Like the eccrine gland, the myoepithelium fulfills dual functions in both providing structural support and pumping out preformed sweat.

β-adrenergic receptors and purinergic receptors have been identified on apocrine glands. However, nerve fibers and muscarinc receptors have not been identified, suggesting that any cholinergic stimulation acts humorally.50

Functions

A number of functions have been attributed to the apocrine glands, including roles as odoriferous sexual attractants, territorial markers, and warning signals. These glands play a role in increasing frictional resistance and tactile sensibility as well as in increasing evaporative heat loss in some species. The production of pheromones by the apocrine glands of many species is well established.51

Because the apocrine glands of humans do not begin to function until puberty and are odor producing, it is attractive to speculate that they have some sexual function, which may now be vestigial. There are high levels of 15-lipoxygenase-2 in the secretory cells of the apocrine gland. Its product, 15-hydroxyeicosatetraenoic, a ligand for the nuclear receptor peroxisome proliferator-activated receptor-γ, may function as a signaling molecule and in secretion or differentiation.51 For nonhuman furred primates, apocrine glands may have a purpose in thermoregulation as well.

Composition of Secretion

When it is first secreted, the apocrine sweat of humans is milky, viscid, and without odor. Apocrine sweat contains three types of precursors: fatty acids, sulfanyl alkanols and odiferous steroids, which are converted by bacteria on axillary skin, particularly corynebacterium striatum, into odiferous substances. Secretion of amino acid and steroid precursors is controlled by an ATP-dependent efflux pump multidrug resistance protein 8 (MRP8), encoded by the gene ABCC11, which is expressed in apocrine sweat glands. Axillary odor is significantly reduced in Asian populations that carry a single nucleotide polymorphism (SNP) in this gene, which also affects earwax characteristics.52

Mode of Secretion

Apocrine (decapitation), holocrine and merocrine types of secretion have been reported in apocrine glands. Cannulation of the duct of the human apocrine sweat gland has shown that secretion is pulsatile, and it is assumed that contractions of the myoepithelial cells surrounding the secretory cells are responsible for these pulsations.53

Control of Secretion

The apocrine sweat glands of humans respond to emotive stimuli only after puberty. They can be stimulated by either epinephrine or norepinephrine given locally or systemically. Studies have shown that the apocrine glands are controlled mainly by adrenergic agonists52; although some cholinergic control also has been reported.49,54 This is in contrast to the eccrine glands, which are under cholinergic control.

Although an intact nerve supply is a functional requirement of apocrine sweating, the demonstration of nerve endings or varicosities in close proximity to the glands has been difficult.49,55 Local capillary circulation likely assists in conveying transmitter substance to the sweat gland cells, a form of neurohumoral transmission.

As would be expected, drugs that affect adrenergic systems also have an effect on apocrine sweat glands. Adrenergic neuron-blocking agents inhibit sweating, as do drugs that deplete the stores of transmitter substance in adrenergic neurons. Drugs that block specific adrenergic receptors also inhibit sweating, but the types of receptors that must be blocked differ in various species. The type of receptor that mediates the response of the apocrine glands of humans has not been elucidated.