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

CONTINUING MEDICAL EDUCATION

Wilma F. Bergfeld, MD

GOAL To understand the pathophysiology of acne vulgaris in children and adolescents

OBJECTIVES Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Describe the pathophysiology of acne. 2. Explain how adrenarche influences acne. 3. Discuss the role of androgens in the development of acne.

CME Test on page 112.

This article has been peer reviewed and is accredited by the ACCME to provide continuing approved by Michael Fisher, MD, Professor of medical education for physicians. Medicine, Albert Einstein College of Medicine. Albert Einstein College of Medicine designates Review date: July 2004. this educational activity for a maximum of 1 This activity has been planned and implemented category 1 credit toward the AMA Physician’s in accordance with the Essential Areas and Policies Recognition Award. Each physician should claim of the Accreditation Council for Continuing Medical only that hour of credit that he/she actually spent Education through the joint sponsorship of Albert in the activity. Einstein College of Medicine and Quadrant This activity has been planned and produced in HealthCom, Inc. Albert Einstein College of Medicine accordance with ACCME Essentials.

Dr. Bergfeld reports no conflict of interest. The author reports no discussion of off-label use. Dr. Fisher reports no conflict of interest.

Microcomedones, the earliest lesions of acne, are produced and colonization of follicles by appear at adrenarche, which typically occurs at Propionibacterium acnes increases. Inflamma- about 8 years of age when androgens of adrenal tory lesions, such as pustules, papules, and origin begin to stimulate follicular hyperkeratosis nodules, are the result of the host’s immune and sebaceous hyperplasia in pilosebaceous responses to P acnes; the proinflammatory units on the face. Comedones appear about cytokines are released by immunocompetent 2 years later, when androgens of gonadal origin leukocytes that are recruited in response to this bacterium and its metabolic by-products. Andro- gens also affect the barrier function of the skin, Accepted for publication June 14, 2004. and disturbances of barrier function may stimu- Dr. Bergfeld is Head, Dermatological Research, Department late epidermal DNA synthesis. This leads to epi- of Dermatology, Cleveland Clinic, Ohio, and Clinical Associate dermal hyperplasia, which may also contribute to Professor, Department of Dermatology, Case Western follicular hyperkeratosis in acne. Optimal treat- University, Cleveland. ment for this disorder will address these various Reprints: Wilma F. Bergfeld, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, A61, Cleveland, OH 44195 pathophysiologic factors. (e-mail: [email protected]). Cutis. 2004;74:92-97.

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cne is predominantly a disorder of late acnes; and perifollicular inflammation.5-13 Follicular childhood and adolescence, despite the fact hyperkeratinization, sebocytic hyperplasia, and A that it may persist into, recur, or begin dur- seborrhea are all dependent on androgens.14-16 ing adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,1 Role of Adrenarche and even earlier in those with abnormal viriliza- The pathogenetic process appears to commence tion or precocious puberty,2 most cases occur with androgenic hormonal stimulation of piloseba- between the ages of 14 and 19 years.1 The preva- ceous units, the density of which is greatest on the lence of acne was assessed among 6768 boys and face and scalp (400–800 glands/cm2) and least on girls aged 12 to 17 years in the National Health the extremities (50 glands/cm2).5 Before levels of Examination Survey of 1966 to 1970.3 Based on circulating androgens increase, pilosebaceous physical examinations, only an estimated 27.7% of units consist of soft, fine, unpigmented vellus hairs children were found to have essentially normal and small sebaceous glands.17 Circulating andro- skin, whereas 68.1% had lesions diagnosed as gens bind to androgen receptors that are localized facial acne (minimal requirement for diagnosis was to the basal layer of the outer-root–sheath kerat- sparse comedones with no inflammatory reaction). inocytes of the hair follicle and to sebaceous Prevalence increased with age more rapidly among glands.15 In sexual hair areas, such as the axilla, younger than older youths, from 39% at age pilosebaceous units begin to differentiate into 12 years to 86.4% at age 17 years, and the increase large terminal hair follicles. In sebaceous areas, in prevalence with age was more rapid and consis- such as the face, pilosebaceous units become seba- tent among boys than girls. Although facial acne ceous follicles while the hair remains vellus.17 was about as prevalent among girls as boys in the Without a source of circulating androgens, the 12- to 17-year age range (69.8% and 66.4%, respec- sebaceous glands remain small.6 tively), the onset occurred somewhat earlier in The adrenals and the gonads produce the major- girls, and the severity tended to be greater in boys. ity of circulating androgens.15 During the prepuber- More severe facial acne (defined in the survey as tal period, adrenal androgens appear to be the major at least comedones, small pustules, and a tendency determinant of sebaceous gland activity.18 In both toward inflamed lesions deeper than the follicular boys and girls, plasma concentrations of the adrenal orifice) was present in a much smaller proportion androgens dehydroepiandrosterone (DHEA) and of youths. dehydroepiandrosterone sulfate (DHEAS) normally More recently, estimates from the National begin to increase at adrenarche, or adrenal puberty, Health Interview Survey of 1996, which included which typically occurs at about age 8 years, and 24,371 households containing 63,402 persons, continue to rise through puberty.19 Conditions such identified “chronic” acne (acne with a duration as adrenal hyperplasia or polycystic ovary disease 3 months) in 2.44% of those 17 years and are associated with hyperandrogenism; sudden younger,4 which corresponds approximately with onset of acne or treatment-resistant acne may be the prevalence of “more severe facial acne” in the associated with these conditions.15 earlier survey. These results suggest a relationship Androgen stimulation drives the changes in both between the onset of puberty and the pathophysi- follicular keratinocytes and sebocytes that lead to ology of acne. This article reviews recent advances the formation of microcomedones,10 which are not in our understanding of acne in children and ado- visible but are already present in 40% of children lescents, with an emphasis on the triggering role of aged 8 to 10 years.17 Microcomedones develop when adrenarche. Part 2 of this article will review treat- desquamated cornified cells of the upper canal of the ment options. sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased Pathophysiology of Acne sebum production (retention hyperkeratosis). A number of pathophysiologic factors contribute to The onset of adrenal production of DHEA and the development of acne, beginning with increased DHEAS is followed by a rise in plasma levels of prepubertal androgen production, followed in a adrenal androstenedione 1 to 2 years later, which generally sequential manner by abnormal pilose- approximately coincides with an increase in baceous follicular keratinization and desquama- gonadal testosterone production—the so-called tion; increased proliferation of sebocytes, enlarged gonadarche or pubarche. It is at this time that sebaceous glands, and augmented secretion of microcomedones begin to enlarge and become vis- sebum; obstruction of sebaceous follicles; coloniza- ible, forming open and closed comedones, which tion of pilosebaceous units by Propionibacterium are noninflammatory lesions.10 This comedogenesis

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may be driven in part by increased levels of factor.17 For example, Imperato-McGinley and col- interleukin 1, which is derived from ductal kerat- leagues28 showed that patients with an inherited inocytes.20 Colonization of the follicular canal 5 -reductase deficiency and decreased DHT pro- with P acnes, an anaerobic, aerotolerant, duced no sebum, just as preadrenarchal children lipophilic diphtheroid that thrives in triglyceride- produce no sebum. In a 5-year longitudinal study of rich sebum, follows comedogenesis.21 Inflamma- adolescent girls, Lucky and colleagues29 observed a tory acne appears to be the result of the host correlation between early onset of acne, androgen response to P acnes and the proinflammatory levels, and more severe comedonal acne later. Girls cytokines released by immunocompetent cells that who experienced early onset of acne had higher are recruited by this bacterium and its metabolic levels of DHEAS, testosterone, and free testos- by-products.11,13,21,22 Depending on the intensity of terone. The researchers speculated that DHEAS the inflammatory process and its localization appears to be involved in the initiation of acne.29 within the follicle, erythema, superficial pustules, Concentrations of testosterone and DHT can papules, and/or nodules (cysts) may develop.7 be decreased by local conversion to estrogens; to Most patients have a variety of noninflammatory weaker androgens such as 3 -androstenediol; or and inflammatory lesions, though some have pre- to glucuronide conjugates such as 3 -androstanediol dominantly one type or the other.8 It is currently glucuronide, which are more rapidly cleared from believed that hypersensitivity to P acnes deter- the circulation. Fritsch and coworkers30 studied mines the magnitude of the immunologic response messenger RNA expression patterns of the andro- and, accordingly, the severity of inflammatory gen receptor and androgen-metabolizing enzymes acne in individual patients.23 in human skin cells and found that sebocytes are It has been proposed that peptidoglycan and the key regulators of androgen homeostasis. These lipoteichoic acid from the cell wall of P acnes can investigators observed that sebocytes were able to amplify the immune activity of androgen-stimulated both synthesize testosterone from adrenal precur- keratinocytes and sebocytes. This occurs predomi- sors and inactivate it to maintain local concentra- nantly through toll-like receptors with an tions of androgen, whereas keratinocytes only increased release of cytokines such as IL-1, IL-8, inactivate androgen.30 and tumor necrosis factor from these cells.13 Abnormal lipids in sebum also may affect the Plasma Levels of Androgens Versus immune activity of keratinocytes and sebocytes, Androgen Sensitivity thereby directly influencing their proliferation and The severity of facial acne increases with the differentiation and the release of various cytokines. degree of development of secondary sex character- These cytokines, in turn, can activate endothelial istics among boys aged 12 to 16 years and girls aged cells and immunocompetent cells, such as neu- 12 to 15 years, suggesting a relationship with cir- trophils and T lymphocytes, which then partici- culating sex hormones.3 Some patients with facial pate in the inflammatory process. acne have increased levels of circulating andro- Pilosebaceous units are targets for circulating gens, and serum levels of DHEAS are significantly androgens; in addition, they can synthesize the rel- higher in prepubertal girls with both comedonal atively weak androgens DHEA and DHEAS de and inflammatory acne compared with those with- novo from cholesterol.24 Pilosebaceous units also out acne.15 In most cases, however, measurable are able to convert DHEAS to androstenedione variations in circulating androgens do not differen- through the action of 3 -hydroxysteroid dehydro- tiate those persons with either mild or severe acne genase (3 -HSD) and to convert androstenedione from those without acne.7 Rather, the development to the more potent androgen testosterone through of acne appears to depend primarily on end-organ the action of 17 -HSD.25 Testosterone, in turn, sensitivity, or hyperresponsiveness, to normal lev- can be converted by the action of 5 -reductase to els of circulating androgens.1 For example, the dihydrotestosterone (DHT)—the most active activity of 5 -reductase and 17 -HSD in skin androgen metabolite in the pilosebaceous unit26— varies in different regions of the body15; specifi- with an affinity for the androgen receptor that is cally, the activity of 5 -reductase in sebaceous 5- to 10-fold greater than that of testosterone.15 glands of facial skin is greater than that in DHT is primarily responsible for androgen receptor sebaceous glands of skin that is not prone to acne. binding and end-organ effects in the skin,27 and The enzyme 5 -reductase catalyzes the conversion excessive DHT formation in the skin has been of testosterone to the more potent DHT, thereby implicated in the pathogenesis of acne, suggesting suggesting a relationship between increased local that activity of 5 -reductase may be a contributory concentrations of this potent androgen and facial

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acne. In contrast, the oxidative activity of Topical, as well as systemic, flutamide accelerated 17 -HSD is greater in sebaceous glands of skin barrier recovery in controls, indicating that testos- that is not prone to acne. The principal activity of terone directly affects the skin. The investigators this enzyme is to convert testosterone back to the also found that barrier recovery was slower in less active androstenedione, suggesting that local young adult male mice compared with prepubertal concentrations of testosterone remain higher in male mice. The researchers attributed this differ- facial skin than in skin that is not prone to acne. ence to the fact that serum testosterone levels are 60% to 70% lower in prepubertal male mice than Effect of Androgen on the in postpubertal male mice. The investigators also Epidermal Barrier and Keratinocyte demonstrated repeated changes in barrier recovery Proliferation/Differentiation that paralleled peaks and nadirs in serum testos- The stratum corneum is a rate-limiting semiper- terone levels during intermittent hormone replace- meable barrier to the passage of water, electrolytes, ment in a hypopituitary human subject. Finally, the and other molecules between the external envi- investigators studied the ultrastructure of the skin ronment and internal milieu.31 It is composed of of subject animals. Kao et al noted no difference in keratinocytes and a lipid-rich intercellular matrix sebaceous lipid synthesis but did observe that the of sphingolipids, cholesterol, and free fatty acids.32 thickness of the stratum corneum decreased in Lipid synthesis occurs in all nucleated layers of the testosterone-replete animals because of decreased epidermis, and epidermal lamellar bodies then lamellar body formation and secretion.35 deliver the newly synthesized lipids to the inter- The clinical implications of these findings are stices of the stratum corneum, leading to water unclear because skin diseases that may be associ- barrier formation. In addition to androgen’s effects ated with compromised barrier homeostasis appear on the pilosebaceous unit, androgens modulate to be as common in women as men. However, gen- epidermal growth and differentiation, including der may influence the severity rather than the important influences on the intercellular matrix of prevalence of some dermatologic disorders, such as the stratum corneum, which mediates both trans- acne, through its impact on barrier function. For cutaneous water loss and absorption and percuta- example, it has been postulated that follicular neous absorption of foreign substances such as hyperkeratosis in acne may result from a linoleic pharmaceuticals.33 acid deficiency in the follicular epithelium36 and Interestingly, the stratum corneum of a full-term that retention of desquamated cornified cells in human neonate possesses a normal barrier func- the follicular canal is caused by an imbalance of tion, whereas the stratum corneum of a preterm free sterol and cholesterol sulfate in comedonal neonate is thinner and has an insufficiently devel- lipids.37 In addition, acute or chronic disturbances oped barrier function.31 Androgens delay the of barrier function may stimulate epidermal DNA development of this cutaneous permeability barrier synthesis, leading to epidermal hyperplasia, which in utero, while estrogens accelerate barrier devel- also might contribute to follicular hyperkeratosis opment. A gender difference with respect to fetal in acne.32 development of barrier function also has been Yamamoto and coworkers38 examined the role of noted34; male murine fetuses have demonstrated the sebum secretion rate and the lipid content and slower barrier development compared with female barrier function of the stratum corneum in littermates, an effect that was reversible with the 36 patients with acne and 29 controls. The sebum prenatal administration of the androgen receptor secretion rate over 3 hours was significantly greater antagonist flutamide. Flutamide exerts its antian- in patients with moderate acne, but not mild acne, drogenic action by inhibiting androgen uptake compared with controls. Sphingolipids (ceramides and/or by inhibiting nuclear binding of androgens and free sphingosine) in the stratum corneum were in target tissues. significantly different among patients with moder- Based on these observations in fetal skin, Kao ate acne, mild acne, and controls, with the lowest and colleagues35 evaluated the effects of testos- concentrations in patients with moderate acne. terone on barrier homeostasis in adult murine and Similarly, barrier function was reduced to the human skin. Hypogonadal (due to castration or sys- greatest extent in patients with moderate acne, temic flutamide) male mice displayed significantly with lower levels of sphingolipids corresponding to faster barrier recovery at 3, 6, and 12 hours follow- diminished barrier function. These results suggest ing sequential cellophane tape stripping compared that an impaired barrier function caused by with controls; topical testosterone replacement decreased amounts of ceramides may be responsible slowed barrier recovery in castrated male mice. for the formation of comedones because barrier

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dysfunction is accompanied by hyperkeratosis of 14. Webster GF. Acne vulgaris: state of the science. Arch the follicular epithelium.38 Dermatol. 1999;135:1101-1102. 15. Thiboutot D. Hormones and acne: pathophysiology, Conclusion clinical evaluation, and therapies. Semin Cutan Med Acne is a disorder of childhood and adolescence, Surg. 2001;20:144-153. and increasing levels of circulating androgens of 16. Akimoto N, Sato T, Sakiguchi T, et al. Cell proliferation adrenal and gonadal origin seem to trigger the con- and lipid formation in hamster sebaceous gland cells. dition. The pathophysiology of acne includes, in a Dermatology. 2002;204:118-123. somewhat sequential manner, retention hyperker- 17. Deplewski D, Rosenfield RL. Role of hormones in piloseba- atosis, sebaceous gland hyperplasia and increased ceous unit development. Endocr Rev. 2000;21:363-392. sebum production, colonization of the follicles by 18. Stewart ME, Downing DT, Cook JS, et al. Sebaceous gland P acnes, and perifollicular inflammation. The goals activity and serum dehydroepiandrosterone sulfate levels in of therapy are to reverse these pathogenetic events boys and girls. Arch Dermatol. 1992;128:1345-1348. and thereby minimize or prevent acne lesions. 19. Grumbach MM, Styne DM. Puberty: ontogeny, neuroen- docrinology, physiology, and disorders. In: Wilson JD, Part 2 of this article will discuss treatment options for chil- Foster DW, Kronenberg HM, et al, eds. Williams Textbook dren and adolescents based on the pathophysiology of acne. of Endocrinology. 9th ed. Philadelphia, Pa: WB Saunders Company; 1998:1509-1625. REFERENCES 20. Eady EA, Cove JH. Is acne an infection of blocked pilose- 1. Ebling FJ, Cunliffe WJ. Disorders of the sebaceous glands. baceous follicles? implications for antimicrobial treatment. In: Champion RH, Burton JL, Ebling FJ, eds. Textbook of Am J Clin Dermatol. 2000;1:201-209. Dermatology. 5th ed. Oxford, England: Blackwell Scientific 21. Leyden JJ. The evolving role of Propionibacterium acnes in Publications; 1992:1699-1744. acne. Semin Cutan Med Surg. 2001;20:139-143. 2. Street ME, Weber A, Camacho-Hubner C, et al. Girls with 22. Kim J, Ochoa M-T, Krutzik SR, et al. Activation of toll-like virilisation in childhood: a diagnostic protocol for investi- receptor 2 in acne triggers inflammatory cytokine responses. gation. J Clin Pathol. 1997;50:379-383. J Immunol. 2002;169:1535-1541. 3. Roberts J, Ludford J. Skin conditions of youths 12-17 years. 23. Webster GF. Inflammatory acne represents hypersensitivity data from the National Health Survey, 1966-1970. Vital to Propionibacterium acnes. Dermatology. 1998;196:80-81. Health Stat 1. 1976;11:1-66. 24. Chen W, Thiboutot D, Zouboulis CC. Cutaneous androgen 4. Adams PF, Hendershot GE, Marano MA. Current estimates metabolism: basic research and clinical perspectives. J Invest from the National Health Interview Survey, 1996. National Dermatol. 2002;119:992-1007. 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33. Elias PM, Menon GK. Structural and lipid biochemical 36. Downing DT, Stewart ME, Wertz PW, et al. Essential correlates of the epidermal permeability barrier. Adv Lipid fatty acids and acne. J Am Acad Dermatol. Res. 1991;24:1-26. 1986;14:221-225. 34. Hanley K, Rassner U, Jiang Y, et al. Hormonal basis for the 37. Melnik B, Kinner T, Plewig G. Influence of oral gender difference in epidermal barrier formation in the fetal isotretinoin treatment on the composition of comedonal rat: acceleration by estrogen and delay by testosterone. J lipids: implications for comedogenesis in acne vulgaris. Clin Invest. 1996;97:2576-2584. Arch Dermatol Res. 1988;280:97-102. 35. Kao JS, Garg A, Mao-Qiang M, et al. Testosterone per- 38. Yamamoto A, Takenouchi K, Ito M. Impaired water barrier turbs epidermal permeability barrier homeostasis. J Invest function in acne vulgaris. Arch Dermatol Res. Dermatol. 2001;116:443-451. 1995;287:214-218.

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