It has been proposed that peptidoglycan and lipoteichoic acid from the cell wall of P acnes can amplify the immune activity of androgen-stimulated keratinocytes and sebocytes. This occurs predominantly through toll-like receptors with an increased release of cytokines such as IL-1α, IL-8, and tumor necrosis factor α from these cells.13 Abnormal lipids in sebum also may affect the immune activity of keratinocytes and sebocytes, thereby directly influencing their proliferation and differentiation and the release of various cytokines. These cytokines, in turn, can activate endothelial cells and immunocompetent cells, such as neutrophils and T lymphocytes, which then participate in the inflammatory process.
Pilosebaceous units are targets for circulating androgens; in addition, they can synthesize the relatively weak androgens DHEA and DHEAS de novo from cholesterol.24 Pilosebaceous units also are able to convert DHEAS to androstenedione through the action of 3 β-hydroxysteroid dehydrogenase (3 β-HSD) and to convert androstenedione to the more potent androgen testosterone through the action of 17 β-HSD.25 Testosterone, in turn, can be converted by the action of 5 α-reductase to dihydrotestosterone (DHT)—the most active androgen metabolite in the pilosebaceous unit26—with an affinity for the androgen receptor that is 5- to 10-fold greater than that of testosterone.15 DHT is primarily responsible for androgen receptor binding and end-organ effects in the skin,27 and excessive DHT formation in the skin has been implicated in the pathogenesis of acne, suggesting that activity of 5 α-reductase may be a contributory factor.17 For example, Imperato-McGinley and colleagues28 showed that patients with an inherited 5 α-reductase deficiency and decreased DHT produced no sebum, just as preadrenarchal children produce no sebum. In a 5-year longitudinal study of adolescent girls, Lucky and colleagues29 observed a correlation between early onset of acne, androgen levels, and more severe comedonal acne later. Girls who experienced early onset of acne had higher levels of DHEAS, testosterone, and free testosterone. The researchers speculated that DHEAS appears to be involved in the initiation of acne.29
Concentrations of testosterone and DHT can be decreased by local conversion to estrogens; to weaker androgens such as 3 α-androstenediol; or to glucuronide conjugates such as 3 α-androstanediol glucuronide, which are more rapidly cleared from the circulation. Fritsch and coworkers30 studied messenger RNA expression patterns of the androgen receptor and androgen-metabolizing enzymes in human skin cells and found that sebocytes are the key regulators of androgen homeostasis. These investigators observed that sebocytes were able to both synthesize testosterone from adrenal precursors and inactivate it to maintain local concentrations of androgen, whereas keratinocytes only inactivate androgen.30
Plasma Levels of Androgens Versus Androgen Sensitivity
The severity of facial acne increases with the degree of development of secondary sex characteristics among boys aged 12 to 16 years and girls aged 12 to 15 years, suggesting a relationship with circulating sex hormones.3 Some patients with facial acne have increased levels of circulating androgens, and serum levels of DHEAS are significantly higher in prepubertal girls with both comedonal and inflammatory acne compared with those without acne.15 In most cases, however, measurable variations in circulating androgens do not differentiate those persons with either mild or severe acne from those without acne.7 Rather, the development of acne appears to depend primarily on end-organ sensitivity, or hyperresponsiveness, to normal levels of circulating androgens.1 For example, the activity of 5 α-reductase and 17 β-HSD in skin varies in different regions of the body15; specifically, the activity of 5 α-reductase in sebaceous glands of facial skin is greater than that in sebaceous glands of skin that is not prone to acne. The enzyme 5 α-reductase catalyzes the conversion of testosterone to the more potent DHT, thereby suggesting a relationship between increased local concentrations of this potent androgen and facial acne. In contrast, the oxidative activity of 17 β-HSD is greater in sebaceous glands of skin that is not prone to acne. The principal activity of this enzyme is to convert testosterone back to the less active androstenedione, suggesting that local concentrations of testosterone remain higher in facial skin than in skin that is not prone to acne.
Effect of Androgen on the Epidermal Barrier and Keratinocyte Proliferation/Differentiation
The stratum corneum is a rate-limiting semipermeable barrier to the passage of water, electrolytes, and other molecules between the external environment and internal milieu.31 It is composed of keratinocytes and a lipid-rich intercellular matrix of sphingolipids, cholesterol, and free fatty acids.32 Lipid synthesis occurs in all nucleated layers of the epidermis, and epidermal lamellar bodies then deliver the newly synthesized lipids to the interstices of the stratum corneum, leading to water barrier formation. In addition to androgen's effects on the pilosebaceous unit, androgens modulate epidermal growth and differentiation, including important influences on the intercellular matrix of the stratum corneum, which mediates both transcutaneous water loss and absorption and percutaneous absorption of foreign substances such as pharmaceuticals.33
Interestingly, the stratum corneum of a full-term human neonate possesses a normal barrier function, whereas the stratum corneum of a preterm neonate is thinner and has an insufficiently developed barrier function.31 Androgens delay the development of this cutaneous permeability barrier in utero, while estrogens accelerate barrier development. A gender difference with respect to fetal development of barrier function also has been noted34; male murine fetuses have demonstrated slower barrier development compared with female littermates, an effect that was reversible with the prenatal administration of the androgen receptor antagonist flutamide. Flutamide exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgens in target tissues.
Based on these observations in fetal skin, Kao and colleagues35 evaluated the effects of testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal (due to castration or systemic flutamide) male mice displayed significantly faster barrier recovery at 3, 6, and 12 hours following sequential cellophane tape stripping compared with controls; topical testosterone replacement slowed barrier recovery in castrated male mice. Topical, as well as systemic, flutamide accelerated barrier recovery in controls, indicating that testosterone directly affects the skin. The investigators also found that barrier recovery was slower in young adult male mice compared with prepubertal male mice. The researchers attributed this difference to the fact that serum testosterone levels are 60% to 70% lower in prepubertal male mice than in postpubertal male mice. The investigators also demonstrated repeated changes in barrier recovery that paralleled peaks and nadirs in serum testosterone levels during intermittent hormone replacement in a hypopituitary human subject. Finally, the investigators studied the ultrastructure of the skin of subject animals. Kao et al noted no difference in sebaceous lipid synthesis but did observe that the thickness of the stratum corneum decreased in testosterone-replete animals because of decreased lamellar body formation and secretion.35