PERCUTANEOUS ABSORPTION OF ADRENAL STEROIDS 157 have shown that in contrast to hydrocortisone free alcohol no appreciable increase in absorption of cortisone acetate occurs at skin sites from which the barrier is totally removed (21). It is possible, then, that the thera- peutic effectiveness of hydrocortisone free alcohol occurs from the absorp- tion of increased quantities of hormone through sites of inflammatory damage to the barrier. In contrast, cortisone acetate may be unable to penetrate areas with diminished barrier function any more effectively than normal skin sites. Another possible explanation is that the small amounts of cortisone acetate which do penetrate the barrier are metabolically inactivated in the skin too rapidly to exert appreciable anti-inflammatory effects. Lastly, it is conceivable that the skin may be capable of altering hydro- cortisone metabolically to yield one or more intermediate compounds primarily responsible for the hormone's anti-inflammatory effects, while cortisone cannot be similarly metabolized. This theory was originally pro- posed by Wilson, et aL (42), to explain the therapeutic disparity observed with injections of hydrocortisone and cortisone into the synovial cavity. Initial studies on the metabolic alteration of adrenal steroids and observa- tions of differing rates of metabolism of these compounds in human skin have recently been reported (43). One of the most puzzling problems relating to the topical effectiveness of adrenal steroid therapy is the selective nature of the cutaneous disorders affected. Furthermore topical steroid treatment is regularly without etTect even in certain dermatoses--such as psoriasis and exfoliative derma- titis--in which histologic changes somewhat similar to those of eczematous dermatoses are found. Thus it appears that the barrier may behave quite differently in various dermatologic disorders. Another problem concerns the impressive response to systemic administration of these hormones in con- trast to absent local effects in such dermatoses, for example, as pemphigus vulgaris and exfoliative dermatitis. The explanation for this observation apparently lies either in differences of absorption or in differences of cutaneous versus systemic metabolism of adrenal steroids in various dermatologic disorders. Comparisons of the absorption of hydrocortisone from skin and mucous membrane sites (19) reflect the far greater permeability of mucous mem- brane surfaces. No layer comparable to the superficial epidermal barrier has been demonstrated for mucous membrane epithelium and the factors governing absorption through such epithelial sites must be somewhat difFer- ent from those influencing percutaneous absorption. Penetration of mu- cous membrane layers may be basically determined by cellular membrane permeability throughout, whereas for skin this factor is of decisive impor- tance primarily in the cells of the superficial barrier and the pilosebaceous apparatus. The factors governing absorption of substances through

158 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS mucosal surfaces, particularly in the lower intestinal tract, have received less study than those relating to the penetrability of skin. On the other hand the effects of bacterial action on exogenous materials applied directly to the skin have received little attention, particularly in reference to percutaneous absorption. The influence of bacterial action on substances instilled into the rectum has already been described in refer- ence to 6-methylprednisolone (35). Investigations of the metabolism of topical adrenal steroids by the bacterial flora of the skin might be of partic- ular interest in regard to the physiological effects of these altered com- pounds. A recent study has shown that rectal infusions of hydrocortisone are followed by a marked increase in urinary excretion of 17-ketosteroids as a result of bacterial enzymatic metabolism of the steroid in the bowel (44). Weak androgenic activity has been attributed to one of the metabolites excreted. This observation, too, suggests that an investigation ofadrenal steroid metabolism by the cutaneous bacterial flora could provide further information on the pathogenesis of steroid ache following systemic adminis- tration of these hormones. The pronounced atrophy and inhibition of hair growth noted after topical administration of cortisone and hydrocortisone to rat skin (9, 25, 26) indicate that the hair cycle in these animals is in some way influenced by adrenal steroids. This observation was supported later by the findings of Herrmann, et al. (45) and by the investigations of Mohn (46). The earlier work of Whitaker and Baker (47, 48) and more recent studies (49) have recorded the relative potency of individual adrenocortical steroids in inhibiting hair growth in animals following topical application. Although spontaneous release of inhibition subsequently occurs despite continued administration of these hormones, the mechanism of suppression of cyclic activity remains to be elucidated. SUMMARY The data pertaining to the percutaneous absorption of adrena] steroids has been reviewed. The implications of the findings described for further investigative work both in the field of percutaneous absorption and in less closely related areas has been stressed. REFERENCES (1) Sulzberger, M. B., and Witten, V. H., y. Invest. Dermatol., 19, 101 (1952). (2) Sulzberger, M. B., Witten, V. H., and Smith, C. C., y. zfm. Med. zfssoc., 151, 468 (1953). (3) Robinson, Jr., H. M., and Robinson, R. C. V., Ibid., 155, 1213 (1954). (4) Malkinson, F. D., and We]k, G. C., Brit. y. Dermatol., 66, 300 (1954). (5) Frolow, G. R., Witten, V. H., and Sulzberger, M. B., zfrci. Dermatof., 76, 185 (1957). (6) Frank L., and Stritzler, C.,fbid., 72, 547 (1955). (7) Zimmerman, g. I-]., y. zfm. Med. zfssoc., 162, 1379 (1956). (8) Smith, Jr., J. G., Zawisza, R. J., and Blank, H., zfrcl. Dermatol. and $ypMfol., 78, 643 (1958). (9) Castor, C. W., and Baker, B. L., Endocrinology, 47, 234 (1950). (10) Baker, B. L., Ingle, D. J., Li, C. H., and Evans, H. M., Anat. Record, 102, 313 (1948).