86 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ber of unrelated lipoid-soluble sub- stances which had reactive --C = C- bonds in common. Therefore, our attention was immediately turned to one of the most important lipoid- soluble, unsaturated natural com- pound, vitamin A. Vitamin A, synthetic or natural, caused reversible hair loss in mice or rabbits after a single local ap- plication of massive doses. Again the effect was reversible. The first definite evidence was obtained that the depilatory action was con- nected with the presence of un- saturated double bonds in the mole- cule, when hydrogenation of vita- min A (leading to perhydro-vitamin A) abolished the depilatory activity. In addition, vitamin A had two unique properties as a depilatory agent: (1) It was the only un- saturated, lipoid-soluble depilatory compound encountered so far which did not inactivate sulfhydryl com- pounds in vitro. (2) When in- gested in excessive amounts over long periods of time, vitamin A caused reversible hair loss also in human beings. These findings led us to a re- evaluation of the currently pre- vailing concepts regarding the mode of action of massive doses of vitamin A upon the skin. Doses of 100,000 units/day have been used routinely in the treatment of a number of cutaneous diseases characterized by abnormal or excessive production of horny material. It has been assumed that these conditions of abnormal keratinization were due to avitaminosis A, because they were frequently benefited from mas- sive doses of the vitamin. Since in many of these skin diseases there were no classical signs of a general vitamin A deficiency (such as night- blindness or low plasma vitamin A level), it was claimed that there could very well exist a localized vitamin A deficiency, limited only to the skin. It was believed that such an isolated organ deficiency was caused by impaired transporta- tion of, utilization of, or increased demand for, the vitamin by the skin. This hypothetical organ de- ficiencywas named"dysvitaminosis." This theory did not take into ac- count the fact that at no point has it ever been shown that the epider- mis metabolized or even contained vitamin A. In spite of its com- pletely fictitious nature, the concept of "dysvitaminosis" has gained wide acceptance and has profoundly in- fluenced the thinking of many der- matologists. Our clinical and experimental findings with vitamin A led to an entirely different concept of the mode of action of massive doses of this vitamin in cutaneous metabo- lism. Similar interpretations were partially indicated by some authors in the past. The essential ele- ments of our •onclusions may be summarized as follows: 1. The effect of massive doses of vitamin A is a drug effect and not a vitamin effect, a pharmaco- dynamic and not a physiologic action. Hence when a cutaneous disease is favorably influenced by large doses of this vitamin, this in

EXPERIMENTAL LOSS OF HAIR 87 itself is insufficient evidence to classify the disease as a vitamin deficiency. 2. The effect of vitamin A is a direct, local effect upon the epider- mis and apparently consists of some sort of suppressire action on keratin formation. Hence, topical appli- cation of vitamin A preparations is often successful when systemic ad- ministration fails. The usefulness of this method of treatment has been definitely ascertained in a number of cases. A great deal of work re- mains to be done, before the exact indications and preparations to be used will become better established. 3. Preliminary experiments seem to indicate that this direct local pharmacologic action of large doses of vitamin A is not specific. These last findings suggest that it is con- ceivable that in the future, therapy of certain skin conditions will be- come enriched with heretofore ne- glected or unknown preparations. The other important natural sub- stance which had a local depilatory effect in animals, was human sebum, the fatty secretion produced by the sebaceous glands of the skin. The basic experiment is extremely simple. Hair from barber shops is extracted with a fat solvent, such as ether, chloroform, or acetone. The ex- tract is filtered and the solvent evaporated. When the hair fat thus obtained is painted but once onto the skin of rabbits or mice, the hair falls out at the site of ap- plication in about ten to twelve days. As in the case of all the other unsaturated depilatory compounds, baldness from sebum is reversible. Fractionation of human sebum revealed that the depilatory action resided both in the unsaponifiable and saponifiable fractions. We have thus far identified 3 depilatory components in human sebum. These compounds are squalene, an unsaturated hydrocarbon and prob- able precursor of cholesterol, in the unsaponifiable fraction oleic and linoleic acids, both unsaturated fatty acids, in the saponifiable fraction. Again, as in the case of vitamin A, hydrogenation abolished the depilatory action of the unsat- urated depilatory components of human sebum. Thus perhydro-or dodecahydro-squalene was inert stearic acid, the saturated derivative of oleic and linoleic acids, had no depilatory effectiveness. Human se- bum itself and its depilatory com- ponents inactivated free sulfhydryl compounds in vitro hydrogena- tion abolished this property. On the other hand, saturated fractions of human sebum had no effect on hair growth or sulfhydryl corn •- pounds. The finding that sebum inter- feres with hair growth represents the first instance in which a normal constituent of the skin has been shown to influence the processes of hair formation and epidermal keratinization. The full signifi- cance of this observation cannot be assessed at present without indulg- ing in some, possibly unwarranted, speculation. This discovery may offer the first chemical clue to the cause of human baldness. The