The Pathophysiology of Acne Vulgaris in Children and Adolescents, Part 1

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

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

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

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

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

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

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.