Sweating-and-Sweat-Detoxification

Physiology of Sweat Gland Function

Abstract

Review the physiology of sweat gland function and the mechanisms determining sweat amount and composition.
Provide an overview of the thermoregulatory functions and adaptive responses of sweat glands.
Discuss the evidence for potential non-thermoregulatory roles of sweat in maintaining or perturbing human health.

Introduction

Sweat evaporation is critical for thermoregulation, especially during strenuous activity or heat exposure.
Compromised sweating (e.g., anhidrosis, encapsulating clothing) leads to rapid core temperature increases and potential heat exhaustion or stroke.
Common perceptions include sweating as an excretory function (like the renal system) for clearing micronutrients, waste, and toxicants.
This belief leads to practices like prolonged sauna use or exercise in extreme conditions to induce heavy sweating for perceived health benefits.
However, the effectiveness of sweat glands as an excretory organ is unclear.
Another common idea is that excreting sweat can lead to micronutrient imbalances.

Types of Sweat Glands

Three main types: eccrine, apocrine, and apoeccrine.

Eccrine Sweat Glands

Most numerous and widely distributed, responsible for the highest sweat volume.
Discovered in the 1830s but named later by Schiefferdecker.
Humans have ~2-4 million eccrine glands on both glabrous (palms, soles) and non-glabrous (hairy) skin.
Density varies: highest on palms and soles (~250-550 glands/cm $^2$ ), responding to emotional and thermal stimuli.
Non-glabrous skin has lower density but covers a larger area, primarily for thermoregulation.
Functional early in life, with the total number fixed around 2-3 years of age.
Sweat gland density decreases with skin expansion during growth and is inversely proportional to body surface area.
Children have higher densities than adults; larger individuals have lower densities.
Variability in sweating rate is due to sweat secretion rate per gland, not the number of active glands.
Eccrine sweat is mostly water and NaCl, plus other chemicals from interstitial fluid and the gland itself.

Apocrine Sweat Glands

First recognized by Krause in 1844, named later by Schiefferdecker in 1922.
Located mainly in the axilla, breasts, face, scalp, and perineum.
Larger than eccrine glands and open into hair follicles.
Secretory function starts at puberty.
Produce viscous, lipid-rich sweat containing proteins, sugars, and ammonia.
Involved in pheromone production (body odor), though rudimentary in humans.
Respond equally to adrenergic and cholinergic stimuli.

Apoeccrine Sweat Glands

Recently described by Sato et al. in 1987.
Develop from eccrine glands between ages ~8 to 14, up to 45% of axillary glands by 16-18.
Intermediate in size, with properties of both eccrine and apocrine glands.
Limited to the axillary region.
Distal duct connects and empties sweat directly onto the skin surface, similar to eccrine glands.
Produce copious salt water secretions like eccrine sweat.
Function is unknown, but unlikely to play a significant role in thermoregulation.
More sensitive to cholinergic than adrenergic stimuli.

Sebaceous Glands

Not sweat glands, but secretions impact sweat composition.
Described by Eichorn in 1826.
Associated with hair follicles, present over much of the body, especially the scalp, forehead, face, and anogenital area.
Absent on palms and soles.
Holocrine glands that secrete viscous, lipid-rich fluid of triglycerides, wax esters, squalene, cholesterol, and cholesterol esters.
Sebum production is related to the number and size of glands, under hormonal (androgen) control.
Sebum has antibacterial and antifungal properties and may function as a pheromone.

Structure and Function of Eccrine Sweat Glands

Anatomy

Secretory coil and duct made of simple tubular epithelium.
Secretory tubule is continuous and coiled with the proximal duct.
The distal duct is relatively straight and connects with the acrosyringium in the epidermis.
The secretory coil has three types of cells: clear, dark, and myoepithelial.
- Clear cells secrete primary sweat, which is nearly isotonic with blood plasma; contain intercellular canaliculi, glycogen, and large amounts of mitochondria and Na-K-ATPase activity.
- Dark cells have dark cell granules in the cytoplasm; their function is poorly understood but may act as a repository for bioactive materials involved in regulation of clear cell and duct cell function.
- Myoepithelial cells provide structural support for the gland against hydrostatic pressure during sweat production.
The duct has two cell layers: basal and luminal cells; its primary function is reabsorption of Na and Cl ions as sweat flows through the duct, resulting in hypotonic final sweat.
- Most NaCl reabsorption occurs in the proximal duct, as these cells contain more mitochondria and Na-K-ATPase activity.

Mechanisms of Secretion

Na-K-2Cl cotransport model: Acetylcholine binds to muscarinic receptors on the clear cell basolateral membrane, triggering intracellular Ca release and extracellular Ca influx.
Efflux of KCl through Cl channels in the apical membrane and K channels in the basolateral membrane, leading to cell shrinkage.
Influx of Na, K, and Cl via Na-K-2Cl cotransporters on the basolateral membrane.
Na and K efflux via Na-K-ATPase and K channels on the basolateral membrane and Cl efflux via Cl channels on the apical membrane.
Increased Cl concentration in the lumen creates an electrochemical gradient for Na movement across the cell junction.
Net KCl efflux from the cell creates an osmotic gradient for water movement into the lumen via aquaporin-5 channels.

Ion Reabsorption

Modified Ussing leak-pump model: Passive influx of Na occurs through amiloride-sensitive epithelial Na channels on the luminal cells' apical membrane.
Active transport of Na across the basolateral membrane of the basal cells occurs via Na-K-ATPase, accompanied by passive efflux of K through K channels on the basolateral membrane.
Movement of Cl is largely passive via cystic fibrosis membrane channels (CFTR) on both the apical and basolateral membranes.
The two cell layers are thought to be coupled and behave like a syncytium.
The sweat duct also reabsorbs bicarbonate, either directly or through hydrogen ion secretion, but the specific mechanism is unknown.
Na-K-ATPase activity is influenced by the hormonal control of aldosterone.
The rate of Na, Cl, and bicarbonate reabsorption is flow-dependent; higher sweating rates are associated with proportionally lower reabsorption rates, resulting in higher final sweat electrolyte concentrations.

Sweat Gland Metabolism

Transport of Na across cellular membranes is an active process, thus sweat secretion in the clear cells and Na reabsorption in the duct require ATP.
The main route of energy production for sweat gland activity is oxidative phosphorylation of plasma glucose.
Cellular glycogen is also mobilized in the eccrine sweat gland during sweat secretion, but its absolute amount is too limited to sustain sweat secretion.
Sweat gland depends almost exclusively on exogenous substrates, especially glucose, as its fuel sources.
Although the sweat gland is capable of utilizing lactate and pyruvate as energy sources, these intermediates are less efficient than glucose.
Arterial occlusion of forearms and removal of glucose and oxygen from the bathing medium of isolated sweat glands inhibits sweat production.
Lactate (as an end product of glycolysis) and NaCl concentrations in sweat rise sharply.
Oxygen supply to the sweat gland is important for maintaining sweat secretion and ion reabsorption.

Control of Eccrine Sweating

Primarily respond to thermal stimuli; particularly increased body core temperature, but skin temperature and associated increases in skin blood flow also play a role.
An increase in body temperature is sensed by central and skin thermoreceptors and this information is processed by the preoptic area of the hypothalamus to trigger the sudomotor response.
Recent studies suggest that thermoreceptors in the abdominal region and muscles also play a role in the control of sweating.
Thermal sweating is predominantly mediated by sympathetic cholinergic stimulation.
Sweat production is stimulated through the release of acetylcholine from nonmyelinated class C sympathetic postganglionic fibers, which binds to muscarinic (subtype 3) receptors on the sweat gland
Eccrine glands also secrete sweat in response to adrenergic stimulation, but to a much lesser extent than that of cholinergic stimulation.
Catecholamines, as well as other neuromodulators, such as vasoactive intestinal peptide, calcitonin gene-related peptide, and nitric oxide, have also been found to play minor roles in the neural stimulation of eccrine sweating.
In addition, eccrine sweat glands respond to non-thermal stimuli related to exercise and are thought to be mediated by feed-forward mechanisms related to central command, the exercise pressor reflex (muscle metabo- and mechanoreceptors), osmoreceptors, and possibly baroreceptors.
Sweating rate over the whole body is a product of the density of active sweat glands and the secretion rate per gland.
Upon stimulation of sweating, the initial response is a rapid increase in sweat gland recruitment, followed by a more gradual increase in sweat secretion per gland.
- Two important aspects of thermoregulatory sweating: the onset (i.e. body core temperature threshold) and sensitivity (i.e. slope of the relation between sweating rate and the change in body core temperature) of the sweating response to hyperthermia.
- Shifts in the sweating temperature threshold are thought to be central (hypothalamic) in origin, whereas changes in sensitivity are peripheral (at the level of sweat glands).

Modifiers of Eccrine Sweating

Several intra- and interindividual factors can modify the control of sweating.
- Enhancement of sweating with heat acclimation and aerobic training has been associated with both an earlier onset and greater responsiveness of sweating in relation to body core temperature.
- Dehydration has been shown to delay the sweating response, as hyperosmolality increases the body temperature threshold for sweating onset; hypovolemia may reduce sweating sensitivity, but this finding has not been consistent.
- Older adults exhibit a lower sweat output per activated gland in response to a given pharmacological stimulus or passive heating compared with younger adults; this decline in sweating occurs gradually throughout adulthood and there are regional differences in the age-related decrement in sweat gland function.
- The decline in sweating rate with aging has been primarily attributed to mechanisms related to a decline in aerobic fitness and heat acclimation, rather than age per se. In addition, lifetime ultraviolet exposure and other environmental factors may have an interactive effect with chronological age in determining sweat gland responsiveness
- Men exhibit higher sweating rates than women due to greater cholinergic responsiveness and maximal sweating rate; while sweat gland density is generally higher in women than men
- Other factors that modify sweating includes maturation, altitude / hypoxia, circadian rhythm, menstrual cycle.

Eccrine Sweat Composition

Methodological Considerations

Accuracy and reliability of study methodology are critical
Depending upon the methodology used, sweat collected from the surface of the skin may contain thermal sweat secreted by the eccrine sweat gland, residual contents of the sweat duct, sebum secretions, epidermal cells, and other skin surface contaminants.
This can lead to artificial elevations in sweat constituent concentrations.
Dermal contamination from extra-sweat NaCl seems to be negligible compared with NaCl contained in the sweat itself, as studies have reported only $0.2 mmol/h$ of Cl on the skin without sweat activity.
Ensure that the conditions of the protocol, including the method of sweat stimulation and anatomical location of sweat collection, are specific to the research question of interest.

Overview of Sweat Composition

Sweat is a very complex aqueous mixture of chemicals.
Although sweat is mostly water and NaCl, it also contains a multitude of other solutes in varying concentrations.

Micronutrients in sweat

Electrolytes Na and Cl are found in the highest concentrations. Other micronutrients include K, vitamins, and trace minerals.

Non-micronutrient ingredients in sweat

Non-micronutrient ingredients include products of metabolism, proteins, amino acids, and toxicants.

Sodium Chloride

Regional sweat [Na] typically ranges from $10 to 90 mmol/L$ , while whole-body sweat [Na] is ~ $20–80 mmol/L$ .
The [Na] and [Cl] of final sweat are determined predominantly by the rate of Na reabsorption in the duct relative to the rate of Na secretion in the clear cells.
Na ion reabsorption is controlled by Na-K-ATPase activity, which is influenced by plasma aldosterone concentration and/or sweat gland sensitivity to aldosterone.
The genomic action of aldosterone may have a stronger impact on inter-individual variations in sweat [Na] than the rapid non-genomic action of aldosterone during exercise in humans.
Both [Na] and [Cl] in sweat are influenced by the availability of CFTR chloride channels; with lower CFTR abundance resulting in less ductal reabsorption and therefore higher final sweat [Na] and [Cl].

Effect of Sweat Flow Rate

Sweat flow rate is another important factor determining final sweat [Na] and [Cl] and of other aspects of sweat composition.
Several studies have confirmed a direct relation between sweating rate and final sweat [Na] and [Cl].
As forearm sweating rate increased (from ~ $0.25 to 0.82 mg/cm^2/min$ ), the rate of Na secretion in primary sweat increased proportionally more than the rate of Na reabsorption along the duct
The absolute rate of Na reabsorption actually increased continuously with increases in sweating rate. However, the percentage of secreted Na that was reabsorbed in the duct decreased with a rise in sweating rate. Therefore, the faster the primary sweat travels along the duct the smaller the percentage of Na that can be reabsorbed.

Bicarbonate, pH, and Lactate

Another important function of the sweat gland is reabsorption of bicarbonate for the maintenance of acid-base balance of the blood.
Exact mechanisms are not fully understood, but it is thought that bicarbonate is reabsorbed directly via CFTR chloride channels and/or hydrogen ions are secreted in the sweat duct.
Bicarbonate reabsorption in the duct is inversely related to sweating rate.
There is a direct relation between sweating rate and lactate excretion rate. However, because of the diluting effect of higher sweat fluid volume, there is an inverse relation between sweating rate and sweat lactate concentration

Sweat Composition as a Biomarker

There has been considerable interest recently in the use of sweat as a non-invasive alternative to blood analysis to provide insights to human physiology, health, and performance.
Perhaps the best example of a sweat biomarker is the use of sweat [Cl] for diagnosis of cystic fibrosis.
Apart from the use of sweat [Cl] for the diagnosis of cystic fibrosis, the application of sweat diagnostics has been limited to date.
The utility of glucose, micronutrients, and other constituents as sweat biomarkers is questionable, especially as a real-time monitoring tool, because correlations between sweat and blood have not been established.
A fundamental issue is that sweat [Na] and [Cl] are known to vary considerably within and among individuals, so its use as a hydration biomarker has questionable validity.
More research is needed to determine the utility of sweat composition as a biomarker for human physiological status.

Physiological Purpose of Sweating

Thermoregulation

Primary physiological function of sweating is heat dissipation for body temperature regulation.
The latent heat of vaporization of sweat is $580 kcal$ of heat per $1 kg$ of evaporated sweat ( $2426 J$ per gram of sweat).
According to heat-balance theory, the amount of sweat production is determined by the relation between the evaporative requirement for heat balance (Ereq) and maximum evaporative capacity of the environment
The primary means by which the body gains heat is from metabolism (which is directly proportional to exercise intensity) and the environment; therefore, these factors are also the primary determinants of sudomotor activity
During conditions of low sweat efficiency (e.g. humid environment), a higher sweating rate than calculated from Ereq may be needed to achieve a given level of evaporation

Skin Health

Thought to play a role in epidermal barrier homeostasis through its delivery of water, natural moisturizing factors, and antimicrobial peptides to the skin surface.
Recent immunohistochemistry studies suggest that sweat glands produce and excrete antimicrobial peptides, pointing to a potential role of sweating in host defense against skin infection

Role in Micronutrient Balance

Sweat gland adjustments in response to deficiency or excess

Heat Acclimation

Salt conservation through a decrease in sweat [Na] and [Cl].
In studies where subjects consumed enough NaCl to replace losses incurred during the repeated exercise-heat stress, sweat [Na] and [Cl] did not change or increased slightly.

Trace minerals

Some suggestions that conservation of sweat trace mineral loss occurs on an acute basis during a single bout of exercise. However, again, this is likely due to skin surface contamination, as studies indicated it to be negligible.

Diet

Sodium chloride

Common perception that Na ingestion influences sweat [Na] or the rate of sweat Na excretion. However, study results to date have been mixed.
Salt deficiency or excess seems to have no effect on sweating rate.

Trace minerals and vitamins

Many, but not all, some studies reported no association between dietary intake of trace minerals (Zn, Fe, Ca, Cu) and their concentrations or excretion rates in sweat.
The impact of diet on sweat mineral and vitamin loss seems to be minimal, at least in healthy individuals with no known deficiencies.

Sweating-induced deficiencies

Sodium chloride

Excessive sweat Na losses can exacerbate decreases in plasma [Na] caused primarily by overdrinking for a long period of time (e.g. during a > 4 h endurance event)
An individual’s sweat [Na] impacts their risk for developing hyponatremia in situations of prolonged thermoregulatory sweating

Trace minerals and vitamins

The balance of the evidence suggests that sweat losses probably contribute minimally to whole-body trace mineral and vitamin deficiencies.
Note that in extreme circumstances excess mineral loss cannot be ruled out as a contributing factor to suboptimal trace mineral status.
Micronutrient supplementation does not seem to be necessary on the basis of sweat excretion during physical activity, provided that dietary intakes are normal

Comparison of Sweat Gland and Kidney Function

Water Conservation and Excretion

The sweat glands share some similarities with the renal system; as eccrine glands have mechanisms to conserve Na, Cl, and bicarbonate losses in sweat.
A vital function of the kidneys is to regulate body water balance, stimulating diuresis with overhydration and antidiuresis with hypohydration and/or heat stress, mediated through changes in renal water reabsorption in response to arginine vasopressin (AVP) concentrations in the plasma
APV does not regulate water loss via the sweat glands as it does in the kidneys

Excretion of toxicants

The notion that sweating is a means to accelerate the elimination of persistent environmental contaminants from the human body has been around for many years. However, there is little evidence to support this claim
The chemicals collected at the skin surface in these studies most likely originated from sebum secretions or epidermal cell contamination, and cannot be attributed to eccrine sweat due to an absence of the chemical in blood samples

Excretion of Ethanol

It does seem that sweat ethanol concentration increases with ethanol ingestion and rises linearly with increases in blood alcohol concentration; supporting the idea that sweat ethanol originates from the interstitial fluid and its concentration is not significantly altered during transport through the duct onto the skin surface.
Sweating likely plays a very small role in alcohol detoxification or hangover cures

Excretion of metabolic waste.

Since some waste products appear in sweat, the eccrine glands are also thought of as an excretory organ; sweat glands do not appear to adapt in contribute to regulation of blood concentrations, therefore there is limited evidence that the sweat glands excretory function makes a substantial contribution to homeostasis

Altered Sweat Gland Function From Conditions and Medications

Certain medical conditions and medications can impact sweating rate and sweat composition.

Conclusions

Eccrine sweat glands have a tremendous capacity to secrete sweat for the liberation of heat during exercise and exposure to hot environments
Eccrine sweat glands reabsorb NaCl and bicarbonate to minimize disruptions to whole-body electrolyte balance and acid–base balance, respectively.
Compared to kidneys, NaCl reabsorption by the sweat glands improves with whole-body NaCl deficits, but the response is somewhat delayed