206 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS tions in numbers of melanocytes or simply on the physiological activities of these cells in forming melanin. Normal skin of all colors, including Negro skin, vitiliginous skin, and albino skin, all contain approximately the same numbers of dendritic melanocyte-type cells. In albinism there is a genetic lack of the enzyme tyrosinase, while in Negro skin there appears to be a genetically controlled hyperactivity of this enzymatic function. The mechanisms by which genetic factors regulate melanin production so as to account for the many normal variations in color, shade, and patterning of melanin pigmentation throughout the animal world-are largely not understood. The rate at which melanin is lost from the skin must also obviously influence its melanin content. Two pathways of excretion of melanin granules are known. One is upward through the epidermis with ultimate loss from the surface along with the physiological shedding of the horny layer. The second is through the corium into macrophages and the lymphatic system. Loss of melanin into the corium is favored under pathologic conditions where the basal layer of the epidermis becomes disrupted by disease, such as occurs in lichen planus, lupus erythematosus, and incon- tinentia pigmenti. Loss of melanin from the surface is favored under con- ditions of increased desquamation. Normally the rate of melanin loss from the epidermis seems to be very slow in view of the minimum latent period of three weeks required for the leukoderma induced by exposure to mono- benzyl ether of hydroquinone to become manifest. •3 In most abnormal conditions where melanin pigmentation of the skin is increased, the numbers of melanocytes are not increased, in contrast with the situation in lentigenes and various pigmented moles and tumors. Hormonal, nutritional, and neural factors also have important effects on melanin pigmentation. Among hormonal influences, pituitary, thyroid, adrenal, and gonadal hormones have all been shown to influence melanin pigmentation in living animals. The anterior and intermediate lobes of the pituitary produce several polypeptide factors which have melanocyte stimulating properties. These are ACTH from the anterior lobe, and alpha and beta MSH from the intermediate lobe. •4 Alpha MSH accounts for the major portion by far of the melanocyte-stimulating activity present in extracts of whole pituitary. The intrinsic melanocyte stimulating potency of ACTH is only a very small fraction of that of alpha MSH. Both alpha and beta MSH have molecular weights of approximately 4,000 and contain about fifteen different amino acids. The complete amino acid sequences in the two MSH factors have been recently elucidated largely by the brilliant work of Lerner and associates24,25, 26, and Li and associates, 27, •8 and it is interesting to note that very similar or identical arrangements of nine amino acids occur in alpha and beta MSH as well as in ACTH. As little as 10- •0 of a gram of pure alpha MSH will bring about darkening of small

SKIN AND HAIR PIGMENTATION 207 pieces of isolated frog skin. Administration of MSH to human subjects brings about generalized hyperpigrnentation resembling that seen in Addison's disease. TM With large doses, darkening may become evident in twenty-four hours. After discontinuing administration of this substance the skin slowly returns to its normal color after several weeks. Studies on the urinary excretion of MSH show that more of this hormone is produced and excreted in Addison's disease and pregnancy than under normal conditions. It appears likely that the melanoses in these conditions are at least partly related to this increased MSH production. The output of MSH by the pituitary is inhibited by hydrocortisone. Although MSH in lower vertebrates primarily causes dispersion of melanin granules in melanocytes, there is some evidence that it also brings about an increased rate of melanin produc- tion. •o It is likely that the latter action predominates in human skin although a slow melanin granule dispersing effect in man is also conceivable. Adrenaline and nor-adrenaline inhibit the action of MSH on melanocytes in lower verte- brates. Clear-cut evidence is not available to show that MSH increases the rate of proliferation of melanocytes, but this is also a likely possibility. The effect of thyroid hormone on pigmentation is not entirely under- stood. Hyperthyroidism in man is often accompanied by some degree of increased pigmentation as well as by an increased incidence of vitiligo. In amphibians and some fowl, thyroxine is essential for normal melanization. •, 82 Steroid sex hormones generally have an augmenting effect on cutaneous pigmentation, although this effect is Sometimes very strikingly restricted to certain regions. The nipples, linea nigra and genital areas in women are especially prone to develop melanosis on exposure to oestrogens, even when locally applied. TM In some species, such as the sparrow •4 and hamster, • specialized melanotic spots in males respond with hyperpigmentation to the local application of testosterone. In man, eunuchoid males given testo- sterone acquire the otherwise deficient ability to tan normally on exposure to sunlight. •' As concerns nutritional influences, trace metals, amino-acids, and some vitamins influence melanin formation. Melanosis often accompanies general starvation. In severe protein deficiency, however, as occurs in Kwashiorkor, deficient production of melanin is observed especially in the hair." Panto- thenic acid and para-aminobenzoic acid are required for normal pigmentation of the hair in some animals, •8 but these vitamins have not been shown to influence human melanogenesis normally. Administration of huge pharmacologic doses of para-aminobenzoic acid to individuals with lympho- blastomatous diseases has, however, on a few exceptional occasions resulted in repigmentation of grey hair. TM An increased tendency to form melanin in the skin is observed in scurvy and pellagra caused, respectively, by ascorbic acid and nicotinic acid deficiencies.