Viewpoint 2

Abstract

Dermatologists primarily attack acne from the outside in. Of the three factors long incriminated in the pathogenesis of acne, sebaceous duct obstruction, infection, and excessive production of sebum (1), first-line therapy focuses on the first two: drying or exfolliating agents are used to keep the duct open, and hygiene, antiseptics, and antibiotics are used to control the infectious element. When all of this fails, a toxic systemic retinoid is used to trigger sebocyte atrophy. Our perspective is that an improved inside-out approach should be developed. The fundamental problem is the sebocyte differentiation that underlies sebum production. Acne will not develop without sebum, and sebum will not be produced without androgenic stimulation of sebocytes. Male-hormone stimulation is a prerequisite and an incitant for acne vulgaris, to paraphrase Hamilton's classic observation on common baldness (2). Androgen is necessary for the growth and development of the sebaceous gland3-5). Common inflammatory acne only occurs when androgens rise at puberty (6). Furthermore, acne is one of the manifestations of hyperandrogenism (7). This underlies about half of the cases of even mild acne in women when it persists into adulthood (8). The vast majority of androgen excess is due to polycystic ovary syndrome (PCOS). PCOS is extraordinarily pleomorphic, lacking the classic anovulatory symptoms and obesity 20–50% of the time (9). The possibility of PCOS is often ignored by dermatologists, although, it not only causes infertility but is associated with the metabolic (insulin resistance) syndrome, which carries cardiovascular risk. Basic research suggests that the compensatory insulin excess independently aggravates the acne. Estrogen-progestin combination pills or antiandrogens are effective treatments because they, respectively, suppress gonadal androgen production or androgen action. However, the side effects make them unacceptable for the most severely affected teenage boys. Targeting the branch point in androgen action that is specific to the sebaceous gland would seem likely to revolutionize the treatment of acne. Unfortunately, nature has not readily revealed much about the postreceptor aspects of androgen action in any of its target glands, the sebaceous gland included. While androgens have a proliferative effect on cultured human sebocytes (10, 11), they have only a minimal effect on differentiation of sebocytes in culture, and this effect pales beside that of peroxisome proliferator-activated receptor (PPAR) agonists (12). PPAR agonists are master regulators of lipid metabolism that, in the presence of insulin, glucocorticoid, and a cyclic AMP generator, initiate differentiation of rat preputial sebocytes (Fig. 1). Intriguingly, the PPAR agonist that increases sebocyte differentiation the most in both cultured rat preputial sebocytes, which are immature, and cultured human SZ95 sebocytes, which are partially mature, is the essential long-chain fatty acid, linoleic acid (11, 13). We suspect that this is because the PPAR agonist aspect of its action is to induce an early aspect of sebocyte differentiation, which brings the sebocyte to the mid-differentiated state at which fatty acids reach the critical level required for them to become signaling molecules for the next step in sebocyte differentiation. Diagram of working hypothesis about the site of hormonal and metabolic signaling in the induction of sebocyte differentiation. Insulin-like growth factor-I partially substitutes for insulin, and growth hormone is synergistic with insulin in inducing sebocyte differentiation. The major site of androgen action is postulated to be late in sebocyte differentiation. Lipid metabolism is the key to sebocyte differentiation, which occurs by the accumulation of lipid droplets. Every model of sebaceous gland hypoplasia, other than that brought about by androgen deprivation, involves defects in lipid metabolism14-17). Of these, the knockout of the melanocortin 5 receptor is particularly interesting because this receptor has been identified in sebocytes (18, 19), where it would seem to mediate the augmentation of androgen-induced sebogenesis by α-melanocyte-stimulating hormone (20). In summary, the root of acne seems to lie at the juncture of hormone action and lipid metabolism in sebocyte differentiation. Optimal acne therapy can only be expected to evolve from research in this area.