Clinical and laboratory studies Effects of topical tretinoin on non-sun-exposed protected skin of the elderly Albert M. Kligman, MD, PhD, * Dora Dogadkina, MS, and Robert M. Lavker, PhD Philadelphia, Pennsylvania Background: Topical tretinoin can alter some cutaneous structural alterations induced by excessive exposure to sunlight. Most human studies have focused on photodamaged or pho- toaged skin. Little, if any, information is available on the effects of tretinoin on chronolog- ically or "intrinsically" aged human skin. Objective: Our purpose was to characterize the clinical and structural changes in non-sun- exposed skin after long-term topical treatment with tretinoin. Methods: Six white women, 68 to 79 years of age, applied 0.025% tretinoin cream to the in- ner aspect of one thigh and vehicle cream to the opposite side, once daily for 9 months. Bi- opsyspecimenswereprocessed forhistochemistrybylight microscopyand for ultrastructural analysis by transmission electron microscopy. Results: Tretinoin treatment produced a marked increase in the viable epidermal thickness and resulted in a more undulatingdermoepidermal junction with prominent rete ridges. Re- turn to a more uniform size and electron density of the basal and spinous keratinocytes was alsonoted.Dermalchangesincludedincreases in glycosaminoglycan deposition, elasticfibers, and new blood vessel formation. Conclusion: Tretinoinsubstantiallyaltered the involutional structural changesin intrinsically aged protected skin. The magnitude of the changes may be evengreater than those described for photodamaged skin. (J AM ACAD DERMATOL 1993;29:25-33.) A report from this laboratory demonstrated that topical tretinoin could partially reverse the struc- tural changes induced by excessive exposure to suo- light. 1 These results were confirmed and expanded in a controlled double-blind study? and a series of investigations.l" Numerous other reports indicate that topical tretinoin can partially reverse the clin- ical manifestations of dermatoheliosis, including re- gression of premalignant lesions. 9 - 25 These clinical observations have been supported by various histo- logic investigations. Bhawan et al. 26 used image analysis to quantify tretinoin effects such as epider- mal acanthosis, decreased melanization, and subepi- From the Department of Dermatology, University of Pennsylvania School of Medicine. Supported in part by a grant from Ortho Pharmaceutical Corp. Accepted for publication Dec. 27, 1992. Reprint requests: Robert M. Lavker, PhD, Department of Dermatol- ogy, University of Pennsylvania School of Medicine, Clinical Re- search Building, Room 235A, 422 Curie Blvd., Philadelphia, PA 19104, *Dr. Kligman is a consultant for Ortho Pharmaceutical Corp. Copyright @ 1993 by the American Academy of Dermatology, Inc. 0190-9622/93 $\,00 + .10 16/1/45172 dermal collagen. Ultrastructural details have been reported by Zelickson et al. 27 and Woodley et al. 28 Increased blood flow, which reflects angiogenesis, has been demonstrated by laser-Doppler velocime- try.29 The diminution of fine wrinkles has been ver- ified by optical profilometry of surface replicas. 30 In addition, studies of the effect of tretinoin on UV-induced photodamage in hairless mice have yielded the same results. 31, 32 UV-exposed mice de- velop a peculiar type of wrinkling that is also corrected.P Photoaged skin is not simply an exaggerated form of the regressive changes that occur with the passage of time. The term extrinsic aging applies to external cumulative damage, mainly_ UV radiation, in con- trast to intrinsic aging, which refers to the involu- tional changes that are a result of the passage of time, sometimes called biologic or chronologie ag- ing. 34 However, this separation should not be held too strictly because extrinsic factors such as sunlight are superimposed on intrinsically programmed events. So far, human studies have focused on the photo- damaged skin of the face and dorsal forearms. The 25