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

PATHOGENESIS OF ACNE VULGARIS 647 values observed in normal individuals (10), and plasma testosterone values have been reported as normal in girls with acne (11). Further- more, both plasma estradiol and plasma estrone levels were significantly higher in the acne group (10). In other words, these findings were just the opposite from what one would have expected if acne were an endo- crine disorder characterized by an androgen preponderance. Thus, there is no evidence that acne is due to hormonal imbalance, at least in so far as sex steroid hormones are concerned. This, however, does not pre- clude the use of estrogens in the therapy of this disease and, as previously stated, estrogens do reduce sebum production. Unfortunately, the dose levels that are required are sufficient to produce feminizing effects in males. For this reason, while estrogens are of use in acne, we use them only in women. In women, if the required dose is given without inter- ruption, irregular menses are likely to occur. Therefore, we currently employ the estrogen-progestogen anovulatory drugs and use those agents which have 100 •g of ethynyl estradiol or its 3-methyl ester (12- 14). The great majority of women will manifest a decrease in sebum production on this dosage of estrogen. However, approximately 2 to 5 months may be required for this effect to occur, and even estrogen, there- fore, is not an ideal agent for the therapy of this disease. The answers to the questions that we have posed provide a basis for developing a simplified concept for the pathogenesis and therapy of acne. Acne is a disease in which there is a specific fuel namely, sebum. More specifically, it is the free fatty acids of sebum that are responsible for the onset of the inflammatory process. It is the control of this fuel which is our primary aim in the therapy of this disease. Ache is a disease in which subjective changes are difficult to follow. On the other hand, in the search for agents which can decrease sebum production or inhibit liberation of free fatty acids we have objective end points to measure. While these measurement techniques are available, we still do not have available the ideal therapeutic agents. REFERENCES (1) Strauss, J. S., and Kligman, A.M., Arch. Derre., 82, 779 (1960). (2) Strauss, J. S., and Poehi, P. E., Ibid., 92,448 (1965). (8) Kellum, R. E., Ibid., 93, 610 (1966). (4) Nicolaides, N., J. Am. Oil Chemists' Soc., 42,691 (1965). (5) Poehi, P. E., and Strauss, J. S., J. Invest. Derre., 43,888 (1964). (6) Strauss, J. S., Kligman, A.M., and Poehi, P. E., Ibid., 39, 189 (1962). (7) Strauss, J. S., and Poehi, P. E., Recent Progr. Hormone Res., 19,885 (1968). (8) Freinkel, R. K., Strauss, J. S., Yip, S. Y., and Poehi, P. E., New Eng. J. Med., 273,850 (1965).