Acne Vulgaris: Recent Advances in Pathogenesis and Treatment

Ivor Caro, MD Chapel Hill, North Carolina

Hormonal factors, particularly androgens, appear to be important in the output of sebum or alters its the pathogenesis of acne vulgaris. The sebaceous glands in acne are composition. Fulton et al3 gave acne more sensitive to normal blood levels of androgens, and are stimu­ patients a special chocolate bar con­ lated to produce more sebum. Corynebacterium acnes in the taining ten times the average amount of chocolate with no significant effect. sebaceous follicles act on triglycerides in the sebum to form free fatty acids which might alter the process of keratinization in the Endocrine Factors follicular canal. A microcomedo is formed which can progress to the Androgens4 clinical lesions of acne. Sebum and its components may also be inflammatory if released into the skin. There are, however, still a Sebaceous glands are very sensitive to androgenic stimulation. At birth the number of unanswered questions relating to acne pathogenesis. glands are often enlarged — probably Currently, therapy of acne vulgaris revolves around topical benzoyl due to maternal androgens. During peroxide and retinoic acid and systemic tetracyclines. Benzoyl most of childhood they are small and peroxide and tetracyclines are antibacterial while retinoic acid is virtually nonfunctioning, but if andro­ comedolytic. Because of these different actions, combined therapy gens are administered, enlargement occurs and acne may develop. Severe appears to be more effective (benzoyl peroxide and/or tetracyclines acne had been known to occur in together with retinoic acid). Topical antibiotics show promise as preadolescents with aplastic anemia new therapeutic agents. treated with androgenic steroids. Males produce ten times more This is a brief review of current a family history of severe acne and a testosterone than females, and males thoughts on the pathogenesis and study in 1958 that demonstrated 98 also produce more sebum than treatment of acne vulgaris. A large percent concordance of acne in identi­ females. In males the glands are amount of information has been cal twins,1 little is known about the normally maximally stimulated and no accumulated about pathogenesis, some genetics of acne. It is such a common increase in sebum production occurs of which is probably irrelevant or disorder (Kligman believes that the after testosterone administration. If misleading. Consequently, the hypoth­ prevalence is 100 percent in adoles­ testosterone is administered to fe­ esis of the pathogenesis of acne which cents2) that it becomes difficult to males, the sebaceous glands enlarge is postulated here remains just that — study the inheritance adequately. and more sebum is produced. The at hypothesis. Acne is probably polygenic in origin sudden appearance of anything more and the sum of the action of many than mild acne in an adult female Heredity genes produces the phenotypic expres­ should, therefore, alert one to the Other than the observation that sion which is then modified by possibility of a masculinizing individuals with severe acne often have external factors. syndrome. There appears to be no increase in Diet plasma androgens in acne patients as

«,the Department of Dermatology, Under normal circumstances, di­ compared to controls.5 The sebaceous Nn.h 01 Medicine, -phe University of etary factors are probably of no enlargement and increased sebum Ren ^arot'na, Chapel Hill, North Carolina, quests for reprints should be addressed to importance in the pathogenesis of production found in acne may be due Sch v?r Car°, Department of Dermatology, acne. There is no evidence that high to increased end-organ sensitivity, ie, Noth 01 Medicine, The University of m Carolina, Chapel Hill, NC 27514. carbohydrate or fat intake increases the sebaceous glands have increased

THE JOURNAL OF FAMILY PRACTICE, VOL. 5, NO. 5, 1977 747 sensitivity to normal blood levels of duced by their respective target acnes (Propionibacterium acnes), (2) androgen. For greatest activity, testos­ organs. However, sebum production Staphylococcus epidermidis, and (3) terone must be converted to 5-alpha falls and remains low with pituitary the yeast-like Pityrosporum ovale and dihydrotestosterone by 5-alpha reduc­ failure even with replacement of P. orbiculare.1 8 tase. A recent report6 indicates that testosterone, thyroxine, and hydro­ It is presumed that organisms play a acne skin performs the conversion 2 to cortisone. This suggests the production role in acne by elaborating lipases 20 times greater than the correspond­ of a separate “sebotrophic hormone.” which split the triglycerides in sebum ing normal skin. This might explain It has been proposed that the posterior to free fatty acids (which have been the increased sensitivity of acne pituitary hormone, beta melanin strongly implicated in the pathogenesis patients’ sebaceous glands to andro­ stimulating hormone (MSH) is also the of acne).19 Marples18 has shown in genic stimulation, but it may just sebotrophic factor. However, Thody et vivo that only C. acnes is of impor- reflect the fact that sebaceous glands al13 could not show increased beta tance in this regard. Voss20 has taken are larger and more active in acne MSH levels in acne patients with a slightly different approach and patients. Recently, a group of individ­ increased sebum production. Beta suggests that sebum is a selective uals has been reported who have a lipotrophin, an anterior pituitary hor­ substrate for growth of bacteria and deficiency of 5-alpha reductase. They mone, has also been proposed as that products of this bacterial growth lack severe secondary male sexual having sebotrophic activity.14 Growth including lipases, free fatty acids and characteristics and also do not develop hormone has also been investigated.12 other enzymes, toxins, irritants, and acne. Sebum excretion rates and acne are antigens all act on the follicular both increased in acromegaly but the epithelium to produce irritation and Estrogen4,8,9 effect on the sebaceous glands might inflammation. There is no evidence that physio­ be nonspecific and due to the general logical levels of estrogen have any somatrophic effect of growth hor­ mone. Problems in this particular area effect on sebaceous gland activity. Sebum Pharmacological doses of estrogen and are far from solved at this stage. contraceptive pills with high levels of Sebum plays an important role in estrogen have been shown to reduce Adrenocortical Hormones the pathogenesis of acne. Sebaceous sebum production. Estrogens applied Adrenal androgens appear to con­ gland activity is signifrcantly increased topically to one side of the forehead tribute significantly to sebaceous gland in acne subjects and the individuals produce a decrease in sebum produc­ development.8 The administration of with the most severe acne have the tion, but, since this also occurs on the dehydroepiandrosterone and delta-4- highest sebum secretion rates.21 It has untreated side, a systemic rather than androstenedione, two potent adrenal been shown that sebaceous gland lipid a topical effect is suggested. If androgens, stimulates sebum produc­ is composed of about 60 percent adequate amounts of androgen are tion.15 Adult male castrates have a triglycerides, 25 percent wax esters, available to the peripheral tissue, estro­ low sebum production rate, although and 15 percent squalene.22 As sebum gens do not suppress sebum it is higher than in normal children is carried to the skin surface through production. who do not produce adrenal androgen. the pilosebaceous canal, partial The administration of prednisone to lipolysis of triglycerides occurs with the formation of free fatty acids. C. Progesterone9 ’10 castrated males causes a reduction in sebum production due to adrenal acnes appears to be important in this Physiological or pharmacological respect by producing lipase. doses of progesterone do not appear to suppression. This does not occur in normal males who produce gonadal Sebum seems to play a role in influence sebaceous gland activity, but producing both the inflammatory and synthetically altered ' steroidal com­ testosterone.1 6 The autogenous gluco­ corticoid (hydrocortisone) does not noninflammatory lesions of acne, pounds with progestational activity do Using the rabbit ear experimental stimulate sebaceous glands. These are show sebum stimulation9 but it may have a permissive action to allow model23 sebum was found to be 10-nortestosterone derivatives and i n testosterone to exert its full effect. comedogenic which suggests, but does they probably retain their androgenic not prove, that sebum has similar properties. They are used as compo­ The oral or topical administration of potent corticosteroids which may pro­ properties on human skin. Free fatty nents of contraceptive pills. acids seem to be more comedogenic duce so-called “steroid acne” does not The clinical significance of the than other fractions of sebum. A study estrogen and progesterone effects is normally increase sebum secretion. These adrenal corticosteroids potenti­ in 19 6 5,2 4 in which sebum or its that the high estrogen pills, which are components were injected into human less used today, tend to improve acne, ate the ability of sebaceous follicles to develop hyperkeratosis and also aug­ skin, showed that whole sebum P®' whereas low estrogen pills may make duced inflammatory changes, but ment the action of testosterone on acne worse. isolated free fatty acids produced even androgen-sensitive tissues17 — and this greater inflammation. However, in a is probably how steroid acne is Pituitary Hormones11,12 recent study2 5 the amounts of free produced. Experimental evidence suggests that fatty acids in pilosebaceous glands in ACTH, gonadotrophin, and thyroid- acne were first determined and this stimulating hormone (TSH) are neces­ Bacterial Factors amount then injected. Minimal inflam­ sary to maintain full sebaceous gland The three main organisms found on mation was produced. These workers activity, probably via hormones pro- the face are (1) Corynebacterium suggest that the inflammatory changes

748 THE JOURNAL OF F A M IL Y P R A C T IC E , V O L . 5, NO. 5, 197' pro du ced in the earlier study were Secondary of keratinizatioh in the follicular related to much higher amounts These result from the rupture and canal. A closed comedo results which (nonphysiological) of injected free reencapsulation of primary come­ either becomes an open comedo or an fatty acids. dones. They are larger and tend to inflammatory lesion. Sebum and free Tetracyclines, widely used in the have irregular shapes. An acne cyst is fatty acids appear to play a role in treatment of acne, produce a reduc­ an example of a polyporous, clustered inciting the inflammatory reaction tion of free fatty acids by decreasing comedo. leading to the formation of pustules the population of C. acnes and pos­ The first change observed30 in the and cysts. This whole scheme is only sibly also by inhibiting bacterial development of the comedo occurs in an hypothesis and other factors are lipase.26 Benzoyl peroxide has also the so-caH^d infra-infundibulum of the probably also of great importance. been shown to decrease the numbers follicle. This region usually produces of C. acnes and to reduce the amount only a thin horny layer which sloughs of free fatty acids. However, recent rapidly. At the onset of comedo Recent Advances in Therapy work27’28 has shown that application formation a granular layer is observed At this time, therapy of acne of lipase inhibitors to skin with a and a much thicker and cohesive vulgaris consists primarily of various dramatic reduction of free fatty acids horny layer is formed. These horn cells combinations of benzoyl peroxide, does not produce any improvement in tend to stick together to form a retinoic acid, and systemic tetra­ the acne. These two recent studies compact mass, the microcomedo. Why cyclines. Topical antibiotics show introduce some doubts about the true this change occurs is unclear but it has promise as new therapeutic agents. importance of free fatty acids in the been suggested that the intercellular pathogenesis of acne. cement that normally binds the cells Benzoyl Peroxide Studies on skin surface lipid com­ together is altered in some way and a position in patients with acne as more permanent bond is formed. Benzoyl peroxide has antibacterial compared to controls have produced There also appears to be an increased properties. Its topical application conflicting data. Acne patients production of horn cells in the infra- causes excellent suppression of C. appear to have higher squalene levels infundibulUm. The combination of acnes with virtual eradication of the than controls, and squalene has been increased adhesiveness and retention organism after two weeks of therapy shown to be comedogenic.23 Some of the cells and the increased produc­ (5 percent benzoyl peroxide applied studies have shown low surface free tion contribute to the formation of twice daily).31 There is a correspond­ fatty acid levels in severe acne,29 again comedones. ing decrease of free fatty acids by casting some doubts on the signifi­ Since the primary change occurs in about 50 percent. Benzoyl peroxide is cance of free fatty acids in acne. the infra-infundibulurri, the comedone also comedolytic;31 Daily application is formed beneath the surface and is of 5 or 10 percent benzoyl peroxide not visible on the surface. It is thus a for two weeks reduces the size of Pilosebaceous Follicles and Come­ rabbit ear comedones by about 50 dones closed comedone and appears clini­ cally as a small noninflammatory percent. Benzoyl peroxide thus has a Acne is a disease of sebaceous papule, the whitehead. Closed come­ dual mechanism of action, anti­ follicles of the face, chest, back, and dones tend to continue to produce bacterial and comedolytic. Therapy is upper arms. Follicles affected by acne horn cells and either rupture or usually begun with 5 or 10 percent have a very small pilary portion with produce infra-infundubula opening to applied at night and increased to more tiny hairs and very large sebaceous produce open" comedones or frequent daily applications. It has glands which drain into a wide canal, blackheads. recently been recommended32 that The comedo is the primary lesion of Closed comedones do not allow the strength of benzoyl peroxide be acne. It is an impaction of horn cells sebum or debris to drain and are more increased to 20 percent (or 20 percent within pilosebaceous follicles. Klig- with 10 percent sulfur) especially for 17 likely to rupture. Open comedones, man classifies comedones as either however, appear to have channels acne of the back and chest. Sulfur has primary or secondary. within them allowing sebum to drain. fallen into some disrepute as it has Even though sebaceous glands become been shown to be comedogenic,33 Primary atrophic when comedones form, they although this has been disputed. These start as microscopic come­ still secrete sebum. With rupture of dones (microcomedones) which de- closed comedones, sebum leaks out Retinoic Acid31 wlop into closed comedones or and presumably incites an inflam­ The two main actions of retinoic whiteheads. Closed comedones are matory response. With open come­ acid which make it so useful in acne small ( 1 to 2 mm), whitish papules dones, sebum is able to drain and vulgaris are: resembling milia. The openings of the inflammatory lesions are less likely to 1. It loosens cell attachments: horn follicles in closed comedones are occur. cells do not stick together to form minute and generally cannot be seen. Much disagreement exists regarding impactions, and comedo formation is Closed comedones in turn evolve the various steps of comedone forma­ prevented. ather into open comedones (black- tion. It is suggested that the sebaceous 2. It stimulates mitotic activity of deads) or inflammatory papules. glands are stimulated to produce adult the follicular epithelium: existing Primary comedones are thus micro- amounts of sebum. C. acnes acts on comedones tend to be expelled and eomedones, closed comedones, and the tri|lycerides of the sebum to form closed comedones are more rapidly °Pen comedones. free fatty acids which alter the process transformed into open comedones.

th e JOURNAL OF FAMILY PRACTICE, VOL. 5, NO. 5, 1977 749 Treatment is started with the 0.05 Topical clindamycin has aisb been Invest Dermatol 62:191, 197^ percent cream applied on alternate found to be effective.38 Tetracycline 10. Strauss JS, K lig m a n A M : The effect of progesterone and progesterorib-like com nights. If no excessive redness and has also been used topically and found pounds on the human sebaceous gland i irritation develops, applications can be to be as effective as oral tetracycline39 Invest Dermatol 36:309, 1961 11. Ebling FJ: H orm onal Control and increased to nightly. Both the physi­ at a 0.5 percent concentration. Similar methods of measuring sebaceous gland activity. J Invest Dermatol 62:161, 1974 cian and the patient should be aware results have been obtained in a multi­ 12. Ebling FJG: The role the pitui­ of the manufacturers’ instructions group study.40 Work with all topical tary in acne. Cutis 17:469, 1976c, 13. Thody AJ, Goolamali §K, Burton regarding the use of retinoic acid, and antibiotics in acne is still experimental. JL, et al: Plasma beta-MSH levels in acne with care, irritation can be reduced to vulgaris. Br J Dermatol 92:43, 1975 14. Shuster S, Thody AJ: The control a minimum. Estrogens3 0 and m easurem ent o f sebum secretion, j Invest Dermatol 62:172, 1974 Estrogens are still used in treating 15. Pochi PE, Strauss JS: Sebaceous Combined Benzoyl Peroxide-Retinoic moderate to severe cystic acne in gland response in m an to th e administration of testosterone, delta-4-androstenedione and Acid Therapy30 women. The most widely used contra­ dehydroisoandrosterone. J Invest Dermatol ceptive pills contain 50 /Ug of estrogen, 52:32, 1969 Because retinoic acid and benzoyl 16. P ochi PE, Strauss JS: Effect of which usually suppresses sebum pro­ peroxide have different actions, their prednisone on sebaceous gland secretion. J duction in most individuals. The very Invest Dermatol 49:456, 1967 combined use has been suggested. It 1 7 . K ligm an A M : A n overview of acne. low estrogen pills do not suppress J Invest Dermatol 62:268, 1974 seems that combined treatment sebum production and higher estrogen 18. Marples RR: The microflora of the reduces C. acnes and free fatty acids to face and acne lesions. J Invest Dermatol pills increase the potential hazards of 62:326, 1974 a greater extent than benzoyl peroxide estrogen. Estrogens should be reserved 19. S h a lita A R : Genesis o f free fatty alone. The mechanism may be that acids. J Invest D e rm a to l 6 2 :3 3 2 , 1974 only for a relatively smdll group of 20. Voss JG : A m icro b ia l etiology of retin o ic acid makes skin more acne? Cutis 17:488, 1976 female patients with relatively severe permeable which increases the tissue 21. C u n liffe W J, S huster S: The rate of cystic acne which has not responded sebum excretion in man. Br J Dermatol concentration of benzoyl peroxide. 81 :697, 1969 to adequate trials of standard therapy. 22. Greene RS, Downing DT, Pochi PE, One regimen is to start with benzoyl On contraceptive pills, sebum output et al: Anatomical variation in the amount peroxide applications in the morning and composition of huhran skin surface decreases slowly and is rarely more lip id . J Invest D e rm a to l 5 4:2 40 , 1970 and to add the retinoic acid several 23. Kligman AM, Wheatley VR, Mills than a 50 percent decrease. The bene­ weeks later in the evening. O H : C o n d o g e n ic ity o f hum an sebum. Arch ficial effect is seen only after some Dermatol 102:267, 1970 24. Strauss JS, Pochi PE: Intracuta- j months; about one third of patients neous injection of sebum and comedones, Systemic Tetracyclines Arch Dermatol 92:463, 1965 fail to respond and others may relapse 25. Puhvel SM, Sakamoto M: A reevalu­ The tetracycline group of anti­ while still on the contraceptive pill. ation of fatty acids as inflammatory agents biotics is the most widely used but in acne. J Invest Dermatol 68:93, 1977 26. Shalita AR, Wheatley V: Inhibition other antibiotics may also be used, eg, Antiandrogens o f p an cre a tic lipase by tetracyclines. J erythromycin. With tetracycline, the Invest Dermatol 54:413, 1970 It would seem logical to use anti­ 27. Fulton JE Jr, Weeks JG, McCarty L: j population of C. acnes is decreased by The inability of a bacterial lipase inhibitor androgens in the therapy of acne 90 percent or more and the proportion to control acne vulgaris. J Invest Dermatol vulgaris. At present the work is 64:281, 1975 of free fatty acids in the surface lipid 28. Fulton JE: Lipases: Their question- entirely experimental. The major prob­ able role in acne vulgaris. Int J Dermatol falls by about 50 percent. The com­ lem, assuming that an effective anti­ 15:732, 1976 bined use of systemic tetracyclines and 29. C unliffe WJ, Tan SG: Acne and the androgen can be developed, is to limit sebaceous glands. Int J Dermatol 15:337, topical retinoic acid, which have dif­ its effect to sebaceous glands. 1976 ferent modes of action, has been 30. Plewig G, Kligman AM: Acne, Morphogenesis and Treatment. New York, shown34 to yield results superior to Springer-Verlag, 1975, p 58 those of either drug used alone. References 31. Kligman AM, Mills OH, McGinley 1. Nierman H: Berhicht uber 230 KJ, et al: Acne therapy with tretinoin in A recent report35 concerns the use fwillinge mit hautkrankhbiten. Z Menschl combination with antibiotics. Acta Derm of high-dose tetracycline in acne. The Vererb Konstit-Lehre 34:483, 1958 Venereol [Suppl] (Stockh) 74:111, 1975 2. Kligman AM: An overview of acne. 32. F u lto n JE , B ra d le y S : Thechoiceof patients had severe treatment-resistent J invest Dermatol 62:268, 1974 vitamin A acid, erythromycin, or benzoyl 3. Fulton JE, Plewig G, Kligman AM: peroxide for the topical treatment of acne, acne and were given 2 gm of tetra­ Effect of chocolate on acne vulgaris. JAMA Cutis 17:560, 1976 3 3 . M ills O H , Kligman AM: Is sulphur cycline daily for 3 to 33 months. Of the 210:2071, 1969 4. Strauss JS, Kligman AM, Pochi PE: h e lp fu l o r h a rm fu l in acne vulgaris? Br 31 patients, 14 cleared and 13 The effect of androgens and estrogens on Dermatol 86:620, 1972 34. M ills O H , M arples RR, Kligman AM- human sebaceous glands. J Invest Dermatol improved greatly. Side effects did Acne vulgaris — oral therapy with tetra­ 39:139, 1962 c y c lin e and to p ic a f th e ra p y w ith vitamin A. occur but the drug had to be 5. Strauss JS, Pochi PE, Downing DT: Acne: Perspectives. J Invest Dermatol Arch Dermatol 106:200, 1972 discontinued in only three patients. 3 5. Baer R L, Leshaw SM, Shalita Art 62:321, 1974 6 . Sansone G, Reisner RM: Differential High-dose tetracycline therapy in severe rates of conversion of testosterone to acne. Arch Derrrigtol 1 12:479, 1976 36. Fulton JE, Jr, Pablo G: Topical Topical Antibiotics dihydrotestosterone in acne and in normal antibacterial therapy for acne. Arc skin: A possible pathogenetic factor in acne. In 1974, Fulton and Pablo36 J Invest Dermatol 56:266, 1971 D e rm a to l 110:83, 1974 . R. 37. Mills pH, Kligman AM, Stewart 7. Imperato-McGinley J, Guerrero L, reported the results of their investiga­ The clinical effectiveness of topical eryt Gautier T, et al: Steroid 5 alpha-reductase tion using topical antibiotics in the deficiency in man: An inherited form of mycin in acne vdlgaris. Cutis 14:93, 19 0 38. Stoughton RB, Resh W: Topic male pseudo-hermaphroditism. Science treatment of acne. The erythromycin clindamycin in the control of acne vu g 186:1213, 1974 group in a simple vehicle reduced the 8 . Pochi PE, Strauss JS: Sebaceous Cutis 17:551, 1976 . cpnf 3 9. Blaney DJ, Cook CH: Topical use« free fatty acid level and improved gland suppression with ethnyl estradiol and diethylstilbestrol. Arch Dermatol 108:210, tetracycline in the treatment of acne. inflammatory lesions. Other workers 1973 D e rm a to l 1 12:971, 1976 0f 40. Frank SM: Topical treatment^ 9. Pochi PE, Strauss JS: Endocrino- acne with a tetracycline preparation , Cutis confirmed the clinical effectiveness of logic control of the development and topical erythromycin (2 percent).37 activity of the human sebaceous gland. J 17:539, 1976

1977 750 THE JOURNAL OF FAMILY PRACTICE, VOL. 5, NO,. 5,