PATHOGENESiS OF ACNE VULGARIS 645 immediate region of the follicular disruption. It is also unlikely that the reaction is due to the escape of keratinous material since the area of rupture is initially quite small. Furthermore, experimental in- j eetions of defatted eomedones promote a foreign-body giant cell re- action (1) such changes are not observed in early follieular rupture. The experimental intradermal injection of surface lipids, most of which is sebum, induces a lymphoeytie infiltrate (1, 2) and it is probable that sebum itself causes the early inflammation of aene. Sebum is a complex lipid mixture. Freshly secreted sebum contains no free fatty adds (3). However, surface collections ordinarily contain approxi- mately one-third free fatty adds, one-third triglyeerides, and one-third nonsaponifiable components (4). When the various fractions of sebum are injected into human skin, the greatest amount of inflammation fol- lows the injection of the free fatty adds, the response being similar to that produced by whole sebum (1, 2). Much less inflammation is pro- dueed by the other components including triglyeerides, wax alcohols, squalene, and cholesterol. Therefore, the fatty adds are the most ir- ritating compounds in sebum. Another line of evidence lending support to the importance of sebum in the inflammatory response was a study of sebum production in a large group of 17- to 21-year-old males (5). Sebum production was found to be higher in those subjects with aene as compared to normal individuals. Moreover, within the group of individuals with aene, sebum production was proportional to the degree of aene, although within the individual groups (i.e., mild, moderate, severe aene) considerable variation in sebum production was observed. More direct evidence of a role for sebum in the etiology of inflamma- tory aene is provided by the therapeutic effect of estrogens and antibio- tics. Estrogens suppress sebaceous gland secretion (6, 7). Accompany- ing this decrease in sebum production there is concomitant improvement in aene. Thus, decreasing the output of sebum lessens the severity of inflammatory aene. This relationship is discussed in more detail sub- sequently. Broad-spectrum antibiotics are also of use in aene. For in- stance, small dosages of tetraeyeline (i.e., 250-500 rag/day) will benefit most eases of inflammatory aene. Tetraeyeline in these doses will de- erease the free fatty adds in sebum (8). The esterified fatty add frae- tion is increased under these circumstances, but the total content of fatty adds is unchanged. When antibiotics are stopped, the free fatty add fraction increases again. Thus, it would appear that by altering the composition of sebum and reducing the concentration of free fatty

646 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS acids, which, as noted above, have been shown to be irritating to the skin, improvement is noted in the clinical disease. All of the evidence cited would indicate, then, that sebum, and more specifically the free fatty acid portion, induces the early inflammatory changes in acne. As the follicular wall undergoes more extensive rup- ture, the keratinous material, as well as the bacteria, escape into the dermis. At this time the character of the inflammatory response changes (1, 2). Giant cells are found as a result of the presence of free horny material in the dermis. Polymorphonuclear leukoeytes also ap- pear in the inflammatory infiltrate, and active phagocytosis of bacterial organisms can be found. Thus, it is possible to identify the excitants of the inflammatory response by observing the cellular response. The second question to be discussed briefly is whether acne is a hor- monal disorder. It is not difficult to cite evidence that might support the concept that acne is in fact an endocrine disease. For instance, ache is absent in children (except in rare instances at the time of birth or secondary to underlying endocrinologic disorders), but appears at puberty. It does not occur in castrated individuals or in eunuchs, yet they may develop ache lesions when they are given testosterone (9). In women there are fluctuations in the appearance of ache under two circumstances which would seem to indicate that there is an endocrino- logic basis for the disease. It is quite common to observe a flare-up just prior to the menses, and ache usually improves during preg- nancy. Ache is also seen in various endocrine diseases characterized by adrenal or ovarian hyperactivity. Finally, there is therapeutic evidence that ache will respond to estrogenic hormone administration. While the above examples can be interpreted as favoring an endocrinologic basis for ache, it is equally easy to account for these observations without the necessity of implicating an abnormal hormonal milieu. The question may be answered by an understanding of the mech- anisms underlying the control of sebaceous gland function. There is no motor innervation of the sebaceous glands their control is hormonal and primarily due to hormonal stimulation from androgens which exert their stimulatory effect directly at the gland site (6, 7). The administration of estrogens, in turn, suppresses sebaceous gland activity (6, 7). How- ever, to date, we have been unable to show that this effect is the result of a direct androgen inhibition at the peripheral tissue. If, then, acne is an endocrine disease, it should be accompanied by an increase in androgen production. In 17-to-21 year-old males with ache we have found that both plasma and urinary testosterone levels were no different from the