I I II

Tretinoin emollient cream: A new therapy for

photodamaged skin
Elise A. Olsen, MD, a H. Irving Katz, MD, b Norman Levine, MD, e Jerome Shupack, MD, a
Meda McCarley Billys, M D ) Steven Prawer, MD, b Jonathan Gold, M D , a
Matthew Stiller, MD, d Laura Lufrano, MS, e and E. George Thorne, M D e
Durham, North Carolina," Fridley, Minnesota," Tucson, Arizona; New York, New York;
Boston, Massachusetts," and Raritan, New Jersey

Background: Tretinoin administered topically in 0.1% concentration has been shown to im-
prove the wrinkling and irregular pigmentation of photoaged skin.
Objective: The purpose of this study was to assess the safety and efficacy of various concen-
trations of tretinoin in a new emollient cream base in the treatment of photoaged skin.
Methods: Three concentrations of tretinoin (0.05%, 0.01%, and 0.001%) in a new emollient
cream formulation were compared with vehicle in a 24-week, double-blind, randomized,
multicenter study of 296 subjects with photodamaged facial skin.
Results: Tretinoin emoUient cream 0.05% gave a significantly better global response to ther-
apy than vehicle (/9 < 0.001), with 68% of subjects exhibiting improvement at the end of
therapy, compared with 43% of subjects in the vehicle group. An excellent or good response
was found in 26% of subjects treated with tretinoin emollient cream 0.05% versus 11% of ve-
hicle-treated subjects. Fine wrinkling, mottled hyperpigmentation, and roughness were more
improved in subjects who received tretinoin emollient cream 0.05% than in vehicle-treated
subjects (p < 0.05). No significant difference was found between vehicle and tretinoin emol-
lient cream 0.01% or 0.001%. Histologic examination showed increases in epidermal and
granular layer thickness, decreased melanin content and compaction of the stratum corneum
after therapy with tretinoin emollient cream 0.05% or 0.01%. Mild to moderate skin reac-
tions, such as erythema, peeling, and burning, were the most common side effects and,
although most prevalent in the group using the 0.05% concentration, generally did not limit
tretinoin use.
Conclusion: Tretinoin emollient cream 0.05% appears to be safe and effective in the treat-
ment of photodamaged skin.
(J AM AcaD DERMATOL1992;26:215-24.)

The potential effectiveness of topical tretinoin for
treating photodamaged skin, initially reported by
Kligman et al., 1 has recently been demonstrated in
three vehicle-controlled studies. 24 To reduce irrita-
tionassociated with topical tretinoin therapy, a new
emollient cream formulation has been developed.
The purpose of this multicenter, double-blind, vehi-
From Duke University Medical Center, Durhama; Minnesota Clinical
Study Center, Fridieyb; University of Arizona Health SciencesCen-
ter, Tucsone;New York University Medical Center, New Yorld; and
R. W. Johnson Pharmaceutical Research Institute, Raritan.e
Supported by the R. W. Johnson Pharmaceutical Rweareh Institute,
Raritan, N.J.
Accepted for publication July 18, 1991.
Reprint requests: Elise Olsen, MD, Duke University Medical Center,
Divisionof Dermatology, Box 3294, Durham, NC 27710.
16/1/32543
cle-controlled study was to evaluate the safety and
efficacy of three concentrations of tretinoin emol-
lient cream (TEC) for the treatment of facial pho-
todamage.
MATERIAL AND METHODS
Subjects
Eighty subjects were enrolled at each of four U.S. study
centers (320 subjects total) between May anti October
1987 after written informed consent was obtained. Eligi-
ble subjects were healthy white persons with mild or
moderate facial photodamage who had not used topical
or Systemic retinoids for at least 30 days before study en-
try. Patients with severe photodamage were excluded.
Photodamagewas graded on a 0 to 9 scale, with 0 = none,
1-3 = mild, 4-6 --- moderate, and 7-9 = severe. This glo-
bal assessment of photodamage primarily rated coarse
and fine wrinkling and hyperpigrnentation. Representa-
215

216 Olsen et al.
tive photographs depicting each arbitrary grade of pho-
tedamage were distributed to each investigator to facili-
tate uniformity of grading.
Treatment
Subjects were equally randomized into four treatment
groups: TEC 0.05% (Renova), TEC 0.01%, TEC 0.001%,
or vehicle (placebo). The three TEC formulations and the
vehicle, supplied in double-blind tubes, were essentially
identical in appearance. The TEC vehicle is formulated
as a water-in-oil emulsion in which the oil phase consists
primarily of light mineral oil.
Subjects were instructed to apply the assigned test
cream to the entire face once each evening for 24 consec-
utive weeks. All topical preparations other than makeup
were suspended for at least 48 hours before study visits
and makeup the day of study visits. Subjects were strictly
advised to stay out of the sun throughout the study and
to apply an effective (minimal sun protection factor
[SPF] of 15) sunscreen when sun exposure could not be
avoided. Sunscreens were not routinely recommended on
a daily basis to minimize accentuation of any potential
irritation. To limit variations in skin care products during
the study, all subjects were given the same brand of soap
(Johnson's BabyBar), moisturizer (PURPOSE Dry Skin
Cream), and sunscreen (SUNDOWN Sunblock with an
SPF of 15). Product substitution, especially to a sunsereen
free ofp-aminobenzoie acid, was frequently made at the
subject's request.
Investigator evaluations
Subjects returned for clinical evaluations at baseline, 2
weeks, 4 weeks, and monthly thereafter for the duration
of the 24-week study. Eight clinical signs of photodamage
were evaluated by the investigators as follows: fine wrin-
kling, coarse wrinkling, mottled hyperpigmentation, len-
tigines, roughness, laxity, telangiectasia, and yellowing.
In addition, an overall severity score for photodamage was
given at e~ch visit. Signs of skin irritation (erythema,
peeling, and dryness) were also noted, All observations
were graded on a 10-point scale defined as follows:
0 = none, I-3 -- mild, 4-6 = moderate, and 7-9 = severe.
Patients were evaluated at the same location and in the
same lighting, usually by a single primary investigator,
but never more than two investigators.
At the end of therapy, the subject's global response to
therapy was assessed by the investigators as excellent
(much improved), good (improved), fair (slightly im-
proved), or poor (no change or worse). Standardized
photographs taken at baseline and 12 weeks and, avail-
able as 8 • 10 inch transparencies, were visually com-
pared to the patient at the final visit to aid in clinical as-
sessment. The three serial photographs (baseline and 12
Journal of the
American Academy of
Dermatology
and 24 weeks) were then evaluated independently by each
investigator for corroboration of this assessment.
Subject evaluations
Subjects answered questions before therapy and at
specified intervals during the study. Factors evaluated
were overall appearance and feel of the skin, small wrin-
Ides, brown spots (blotchiness), texture (roughness),
tightness, and pore size. At the end of therapy, all obser-
vations were assessed in comparison with baseline. For
example, the overall appearance and feel of the skin was
graded as much improved, somewhat improved, the same
or worse, and small wrinkles were graded as much less
apparent, somewhat less apparent, the same, or more ap-
parent. In addition, subjects graded any burning/stinging
and/or pruritus on a 0 to 9 scale at each visit.
Photography
A standardized, table-top photographic system was
used to obtain high-quality color photographs of the face
(front and alternate 45-degree side views) at baseline,
week 12, and week 24. The unit consisted of a movable
chin rest mounted on one end of a 25 • 30 inch wooden
platform, with a 35 mm camera, 90 mm lens, and four
head flash units mounted on the opposite end. All film
originated from the same batch. Processing was per-
formed by a central laboratory by standardized proce-
dures.
Biopsy specimens
A 2 mm punch biopsy specimen was obtained from the
left lateral periorbital area before therapy. A second
specimen was taken after 24 weeks of treatment from an
area immediately adjacent to the baseline biopsy. An at-
tempt was made to obtain specimens from wrinkles to
minimize scarring. Specimens were placzd in Trump's
fixative, embedded in paraffin and Epon, and sectioned at
3 and 1 ~m, respcctivdy, by a central laboratory (Skin
Pathology Laboratory, Boston University School of Med-
icine). Stains used included Fontana-Masson for exami-
nation of melanin, toluidine blue for granular layer eval-
uation, or Polysciences Multiple Stain (PMS) for all
other evaluations.
Slides were assessed in a blinded fashion at the
completion of the study by both computerized image
analysis and conventional light microscopy by a single
observer. For computerized image analysis, the image of
the specimen was projected via an Olympus microscope
and attached video camera to a video monitor where the
area of interest was outlined manually and then processed
by computer software. Features assessed included (1)
stratum corneum morphology, described as basket-weave,
Volume 26
Number 1, Part 1
February 1992 Tretinoin emollient cream for photodamage 217

Table I. Demographic characteristics of subject population

TEC

0.05 % 0.01% 0.001% Vehicle Total

(n ffi 76) (n = 73) (n = 75) (n = 72) (n = 296)
Age (yr)
Mean 42.5 42.6 42.3 42.8 42.5
Range 31-50 30-58 30-50 30-50 30-58
Sex
Male 21 (28%) 22 (30%) 15 (20%) 22 (31%) 80 (27%)
Female 55 (72%) 51 (70%) 60 (80%) 50 (69%) 216 (73%)
Overall severity of photodamage*
Mild 28 (37%) 31 (42%) 28 (37%) 20 (28%) 107 (36%)
Moderate 48 (63%) 42 (58%) 47 (63%) 52 (72%) 189 (64%)
*Mild = 1-3; moderate ffi 4-6.

Table II. Global evaluation of clinical response after 24 weeks of therapy

Percent of subjects
1
TEC 0.05 % TEC 0.01% I TEe 0.001% Vehide
(n = 76) (n = 73) I (n = 75) (n = 72)

Improved 68 49 32 43
Excellent (much improved) 5 0 1 0
Good (improved) 21 7 9 11
Fair (slightly improved) 42 42 21 32
No change or worse (poor) 32 51 68 57
p Value <0.1301" 0.874 0.352
*Statistically significant compared with vehicle based on the relative frequencies of excellent, good, fair, and poor responses.

compact, or both; (2) granular layer thickness, measured
as maximal number of granular cell layers; (3) epidermal
thickness as measured from top of the stratum granulo-
sum to the dermoepidermal junction with calculation of
the enclosed area within a 500 lain specimen; (4) melanin
content, determined by measuring the area of Fontana-
Masson-stained material within a measured length of
sampled interfollicular tissue; and (5) the percentage of
total dermis occupied by elastic tissue. Additional details
of histologic methods used have been described else-
where. 5
Statistical analysis
Two-tailed statistical tests were used to compare each
of the three TEC groups with the vehicle group. The p
value required for statistical significance was adjusted for
three multiple comparisons (TEC 0.05% vs vehicle, TEC
0.01% vs vehicle, and TEC 0.001% vs vehicle) such that
an overall significance level of 0.05 was maintained.6Thus
a p value of 0.017 was required to obtain statistical sig-
nificance for the largest of the three differences, 0.025 was
required for the second largest difference, and 0.05 was
required for the smallest difference. A n y p value less than
or equal to 0.05 but not statistically significant by the
aforementioned criteria was considered marginally sig-
nificant.
Depending on the observation, either a categorical
method of analysis7 (e.g., end-of-therapy global evalua-
tion, subject self-assessments, and change in stratum cor-
neum morphology) or an analysis of variance (e.g., clin-
ical signs and continuous histologic measurements) was
employed, For observations graded on the 0 to 9 scale
(e.g., clinical signs), the week 24 value was subtracted
from the baseline value to calculate the change from
baseline. The mean change from baseline to week 24 in
each TEC treatment group was compared with that in the
vehicle group.
To be eligible for the statistical analyses of efficacy,

218 OIsen et aL
Fig. I. A, Pretreatment appearance and (B) appearance
at week 24 of tretinoin emollient cream 0.05% use. Sub-
ject was graded by investigator as having an excellent re-
sponse at week 24.
subjects were required to have completed at least 16
weeks of therapy and to have completed at least half of
their study drug applications. In addition, subjects were
required to have returned for the week 24 visit within 31
days of the scheduled week 24 date. Of the subjects
included in the efficacy analysis, only those with evaluable
baseline and week 24 skin biopsy specimens were eligible
for the analysis of histologic data.
RESULTS
Of the 320 subjects enrolled, 296 were included in
the statistical analyses of clinical efficacy data (76,
73, 75, and 72 subjects in the T E C 0.05%, 0.01%
0.001%, andvehicle groups, respectively). Of the 24
unevaluable subjects, 21 prematurely discontinued
the study, including two in the T E C 0.05% group, six
in the T E C 0.01% group, five in the T E C 0.001%
group, and eight in the vehicle group. O f these 21
subjects, 13 dropped out for personal reasons, four
Journal of the
American Academy of
Dermatology
Fig. 2. A, Pretreatment appearance and (B) appearance
at week 24 of tretinoin emollient cream 0.05% use. Sub-
ject was graded by investigator as having an excellent re-
sponse at week 24.
discontinued because of an adverse skin reaction be-
fore completing 16 weeks of therapy (one in the TEC
0.05% group, two in the TEC 0.01% group, and one
in the vehicle group), three were lost to follow-up,
and one violated the protocol. In addition, three
subjects who completed the study were excluded
from the efficacy analyses. These include one subject
in the T E C 0.05% group who failed to complete at
least 50% of study drug applications as a result of
skin irritation and two subjects (one each in the TEC
0.05% and 0.01% groups) who were more than 31
days late for their week 24 visit.
The 296 evaluable subjects were between 30 and
58 years old (mean age 42.5 years) (Table I). Sev-
enty-three percent were women and 27% were men.
The overaU severity of photodamage was mild in
36% of subjects and moderate in 64% of subjects.
Most subjects (91%) fell in the category of grade 3-6
Volume26
Number 1, Part 1
February 1992 Tretinoin emollient cream for photodamage 219

photodamage; only 9% had grade 1 or 2 photodam-

age. The four treatment groups were well matched
for these characteristics.
Investigator evaluations
Subjects treated with TEC 0.05% showed signif-
icantly greater global improvement after 24 weeks of
therapy than subjects who received vehicle (Table
II). An excellent or good response was found in 26%
of subjects treated with TEC 0.05%, but 11% or less
of subjects in the other three treatment groups. Ex-
amples of subjects who had a good or excellent re-
sponse to therapy are shown in Figs. 1, 2, and 3.
TEC 0.05% also gave a significant difference from
vehicle (p = 0.002) in reducing the overall severity
of photodamage from baseline to the end of therapy
(Tables III and IV). Neither TEC 0.01% nor TEC
0.001% was significantly different from vehicle in
improving photodamage. The time course of the re-
spense to TEC 0.05% therapy, characterized by a
progressively greater reduction in overall severity
between weeks t2 and 24 of therapy, is shown in
Fig. 4.
Fig. 5 shows the dose-related differences among
treatment groups in the improvement of individual
clinical signs. Mottled hyperpigmentation (p =
0.010), fine wrinkling (p = 0.026), and roughness Fig. 3. A, Pretreatment appearance and (B)appearance
at week 24 of tretinoiu emollient cream use. Subject wag
(p = 0.002) decreased to a greater extent after TEC graded by investigatoras having a good response at week
0.05% therapy than after vehicle therapy. Rough- 24.
ness was also more improved with TEC 0.01% than
with vehicle (p = 0.003). Percentages of subjects
with improvement in mottling, fine wrinkling, and todamage, subjects treated with TEC 0.05% for 24
roughness after TEC 0.05% therapy were 63%, 57%, weeks consistently found greater improvement than
and 42%, respectively, compared with 47%, 38%, those treated with vehicle (Fig. 6). The only statis-
and 22%, respectively, in the vehicle group. The sig- ticaUy significant change was that seen for small
nificant difference from vehicle in roughness after wrinkles (p < 0.001); 72% of subjects treated with
TEC 0.05% and 0.01% therapy was primarily dueto TEC 0.05% reported improvement versus 38% of
results obtained at one of the four study centers; lit- vehicle-treated subjects.
tle difference was noted at the other three centers.
No significant differences from vehicle were found Histologic findings
in the TEC groups with respect to coarse wrinkling, The histologic findings of this study showed that
laxity, telangiectasia, lentigines, or yellowing. therapy with TEC 0.05% and 0.01% significantly
increased epidermal thickness and granular layer
Subject analysis thickness (Fig. 7). The stratum corneum tended to
Table V displays the overall subject self-assess- transform from the usual basket-weave pattern to
ment ratings at the end of therapy. In the TEC compact morphology after 24 weeks in all treatment
0.05% group, 78% of the subjects found improve- groups, but this was greater in the TEC-treated
ment in their skin, versus 70% of those using 0.01%, groups in a dose-related fashion; the transformation
60% of those using 0.001%, and 61% of those using in stratum corneum morphology occurred in 72% of
vehicle. When asked to grade specific signs of pho- subjects in the TEC 0.05% group compared with
 Journal of the
American Academy of
220 Olsen et al. Dermatology

9
| ;
4.5

"~ 3 . 5
0=,==O TEC 0.001%
(D
D..=,.,(3 TEC 0.01%
- ~ TEC 0 . 0 5 %
o9 3

II)
I , , , I, , I 1 ,, , I , , , 1, ,, [ I I =
0
0 4 8 12 16 20 24
Weeks of Therapy
Fig. 4. Mean scores for overall severity of photodamage at each evaluation time for all four
treatments.

Table 111. Improvement in overall severity of photodamage after 24 weeks of therapy: Percentage of
subjects
TEC 0.0~ % III TEC 0.01% TEC 0.001% 11 Vehicle
(n = 76) I (n = 73) (n = 75) I (n = 72)

Improved 51 33 21 28
No change 46 64 77 69
Worse 3 3 1 3
TEC, Tretinoin emollient cream.

Table IV. Improvement in overall severitY of photodamage after 24 weeks of therapy: Mean scores
I
TEC 0.05 % [ TEC 0.01% TEC 0.001% Vehicle
(n = 76) I (n = 73) (n = 75") (n -~ 72)

Mean baseline 3.82 3.96 3.87 4.06

Mean week 24 3.18 3.58 3.59 3.78
Mean change from baseline -0.63 -0.38 -0.28 -0.28
Percent change from baseline 16.5 9.6 7.2 6.9
p Value 0.002" 0.312 0.944
Statistically significant compared with vehicle based on an analysis of the mean change in overall severity grade from basdinr to week 24. "Improved"
is defined as a decrease of ~ l unit from baseline to week 24; "worse" is defined as an increase of ___1 unit from baseline to week 24.

37% in the vehicle group (p < 0.001). Melanin con- cally significant. There was a statistically significant
tent was reduced by 56% in the TEC 0.05% group correlation in the TEC 0.05% group (p--0.007)
and 57% in the TEC 0.01% group compared with between the reduction in melanin content and the
29% in the vehicle group, but this was not statisti- decrease in clinical ratings of mottled hyperpigmen-
V o l u m e 26
N u m b e r 1, P a r t l
F e b r u a r y 1992 Tretinoin emollient cream for photodamage 221

70 I TEC 0.05%
65 p=O.010* r-ITEC 0.01%

5s

Er 45
15
(D
4O
35

25
2O
o 15
10
5
0
Mottled Fine Roughness
Hyperpigmentation Wrinkling
*Statistically significant compared with vehicle
**Statistically significant compared with vehicle
i'Marginally statistically significant compared with vehicle
Fig. 5. Investigator evaluations of fine wrinkling, mottled hyperpigrnentation, and rough-
ness after 24 weeks of therapy for all four treatments.

T a b l e V. Subject self-assessment of global response after 24 weeks of therapy

Percent of subjects

TEC 0.05 % TEC 0.01% TEC 0 . ~ 1 % Vehi~

(n = 76) (n = 73) (n -- 7~) (n = 72)

Improved 78 70 60 61
Much improved 14 10 9 7
Somewhat improved 63 60 51 54
Same 16 25 37 35
Worse 7 5 3 4
p Value* 0.060 0.382 0.745
*Statistical results are based on the relative frequencies of the four responses (much improved, somewhat improved, same, or worse).

tation. There was no appreciable change in elastic
tissue content. The histologic results of this study are
presented in detail elsewhere. 5
S i d e effects
Mild to moderate skin reactions, such as dryness,
peeling, erytherna, and burning/stinging, were more
prevalent in those using the T E C 0.05% versus the
0.0 1% or 0.00 [ % preparations or vehicle (Table VI).
Erythema or subjective discomfort (i.e., burning/
stinging, itching) peaked during the first 2 weeks and
lessened with time, whereas dryness and peeling
peaked at 12 to 16 weeks and tended to be persistent.
In cases of excess skin irritation, subjects were either
permitted to stop therapy temporarily or reduce the
frequency of application (17% of subjects) or were
given a brief course of topical steroids (6% of
subjects). Five subjects withdrew from the study
because of adverse reactions, four of whom com-
pleted less than t 6 weeks of therapy and were thus
ineligible for the efficacy analyses; one subject in the
TEC 0.05% group stopped therapy after 20 weeks
because of moderate to severe skin irritation and
another subject discontinued after 7 weeks from pe-
rioral and seborrheic dermatitis; one T E C 0.01%-
treated subject dropped out after nearly 4 weeks be-
 Journal of the
American Academy of
222 OIsen et al. Derrnatology

Small Wrinkles I
II p<0.001*

Pink/Rosy Tone I I p=0.018 +

. !

Brown Spots I
p = 0.033 +

Texture I! !
(Roughness) I

Tightness I [ ] TEC 0,05%

I
[ ] Vehicle
Pore Size
I 1 .! I l 1 1 I i I I
0 10 20 30 40 50 60 70 80 9O 100
Percent of Subjects Improved
*Statistically significant compared with vehicle
+Marginally statistically slgnificanl compared with vehicle
Fig. 6. Comparison of subject self-assessment results for tretinoin emollient cream 0.05%
and vehicle after 24 weeks of therapy.

Table VI. Comparison of skin irritation at week 2 and week 24 of therapy

Percent of subjects with sign or symptom

Week 2 Week 24
TECO'O5%~ TEC O'Ol% I TECO'O01%
.__t__.___ TEC0.05% I TEC0.01% I TEC0.001% Ve~c~
(n = 7 9 ) / (n = 80) (n = 80) I (n =79) (. = 7s) (. = 74) (n = 75) (, = 7 9
Dryness 53 25 16 18 65 41 24 33
Peeling 38 13 6 4 50 15 15 11
Burning/stinging 43 10 4 4 27 9 9 1
Erythema 34 14 14 16 26 8 11 4
Itching 29 13 l1 8 18 8 8 6

cause of a severe sunburn; one subject reported a se-
vere facial eruption and dryness and discontinued
after 14 weeks; one subject receiving vehicle dropped
out of the study after 4 weeks secondary to a mild
acneiform eruption. In addition to these five sub-
jects, one subject in the TEC 0.05% group missed
more than half of the once-daffy applications as a
result of skin irritation and was not included in the
efficacy analysis.
There was no correlation of degree of clinical ir-
ritation with objective clinical response. In those
subjects judged to have a good to excellent global
response to TEC 0.05% (n = 20), 50% had a max-
irnal irritation grade of 5 or greater (on the 9-point
scale used) and none had a maximal erythema of 5
or greater. In comparison, in those with a poor to fair
response to 0.05% TEC (n = 56), 40% had a max-
imal irritation score of 5 or greater (out of possible
9) and 11% had a maximal erythema score of 5 or
greater.
DISCUSSION
Many visible signs of aging, such as wrinkling,
sallowness, and mottled pigmentation, result prima-
rily from cumulative sun exposure. 8, 9 These clinical
changes are accompanied by characteristic histo-
logic findings such as epidermal dysplasia and der-
mal elastosis. The observation that skin aging is
mediated largely by extrinsic rather than intrinsic
factors was noted by Kligman et al.1 and later by
Volume 26
Number 1, Part 1
February 1992
60
50
40
30
20
10
0
L) a)
-10
-20
O.. -30
-40
-50
-60
Epidermal
Thickness
(No. Cell Layers)
*Statistically significant compared with vehicle (p<0.002)
Fig. 7. Change from baseline to the end of therapy in histologic measurements in each
treatment group.
other investigators, 2"4 who showed that some of the
damage associated with UV exposure could be
reversed by topical tretinoin therapy.
Our results, obtained from 296 subjects treated
with one of three concentrations of tretinoin or ve-
hicle at four U.S. centers, confirm that TEC 0.05%
improves the appearance of photodamaged skin in
some subjects after 24 weeks of once-daily therapy.
Reductions in fine wrinkling, roughness, and mot-
tled (blotchy) pigmentation were the most notable
clinical changes. The 0.05% concentration was
clearly more effective than the two lower concentra-
tions (0.01% and 0.001%), neither of which was sig-
nificantly different from the vehicle. These results
are consistent with those obtained in a similar mul-
ticenter study of TEC conducted by Weinstein et
al. lo
Our clinical findings were supported by histologic
evidence from pretherapy and posttherapy skin bi-
opsy specimens. Changes such as increased epider-
mal thickness, compaction of the normally basket-
woven stratum eorneum, thickening of the granular
cell layer, and decreased melanin content were most
pronounced in those subjects who used TEC 0.05%.
The clinical improvement in mottled hyperpigmen-
tatiot~ in the TEC 0.05% treatment group had a sta-
tistically significant correlation with a diminution in
melanin content in specimens from treated areas.
Wrinkling and skin texture may be influenced by
Tretinoin emollient cream for photodarnage 223
1 TEC 0.05%
[ ] TEC 0.01%
i~1TEC 0.001%
Vehicle
I
Granular Layer Melanin Content
Thickness
one or more of the other epidermal effects such as
increased epidermal or granular layer thickness or
stratum corneum compaction, 2 although there was
no statistically significant correlation seen in this
study.
Although the results obtained with T E C 0.05%
were consistently superior to vehicle in terms of both
global improvement and specific clinical features,
the vehicle group nonetheless had notable improve-
ment. Subjects receiving vehicle had improvement
in their global evaluation, overall severity, and the
individual findings of mottled hyperpigmentation,
fine wrinkling and roughness, as well. The water-in-
oil emulsion vehicle and the ancillary measures used,
such as sunscreens, protective clothing, commer-
cially available emollients, mild soaps, and/or
greater attention to skin care, may all have contrib-
uted to the inaproved appearance of some subjects in
the control group. The natural diminution in pig-
mentation seen from summer to winter, coupled
with the admonishment of sun avoidance, m a y par-
tially explain the decrease in pigment seen at the end
versus the beginning of the study in all treatment
groups.
The incidence of skin irritation was highest in
subjects treated with T E C 0.05% (Table VI). It is
possible that the beneficial effects seen with T E C
may be at least partially related to irritation. How-
ever, the degree of irritation did not correlate with

224 Olsen et aL
clinical efficacy, at least in t h e 0.05% treatment
group. Further study is necessary to fully elucidate
the mechanism of action o f topical retinoids on pho-
toaged skin.
We thank Jag Bhawan, MD, and Aldo Gonzalez-
Serva, MD, for performing the histologic assessments;
Barry H. Schwab, PhD, and Barbara H. Perry, PhD, for
providing statistical support; and the study coordinators
and other research personnel at each of the four centers.
REFERENCES
1. Kligman AM, Grove GL, Hirose R, etal. Topical tretinoin
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