Am J Clin Dermatol 2000 Nov-Dec; 1 (6): 369-374

ORIGINAL RESEARCH ARTICLE 1175-0561/00/0011-0369/$20.00/0

© Adis International Limited. All rights reserved.

A Randomized, Placebo-Controlled Trial of

Topical Retinol in the Treatment of Cellulite
Claudine Piérard-Franchimont,1 Gérald E. Piérard,1 Frédérique Henry,1 Valérie Vroome2 and
Geert Cauwenbergh3
1 Department of Dermatopathology, University Medical Center of Liège, Liège, Belgium
2 Johnson & Johnson Consumer, Brussels, Belgium
3 Skin Research Center, Johnson & Johnson Consumer, Skillman, New Jersey, USA

Abstract Background: Cellulite occurs to varying degrees on the thighs and buttocks of many otherwise healthy women.
Among the many purported treatments for cellulite, only a handful have been tested in clinical trials.
Objective: The aim of this study was to critically explore the reputed effect of topical retinol in the treatment
of cellulite.
Materials and Methods: The study compared the effect of topical retinol to a placebo formulation in a left-right
randomized trial in order to eliminate the massage-effect. The study was conducted in 15 women aged from 26
to 44 years who had requested liposuction to improve mild to moderate cellulite.
Results: After 6-months of treatment, skin elasticity was increased by 10.7% while viscosity was decreased by
15.8% at the retinol-treated site. Such an effect on the tensile properties of skin was more prominent where the
mattress phenomenon was the only evidence of cellulite. The lumpy-bumpy appearance of the skin showed
either little response or was not responsive to the treatment. Although gross microanatomical differences were
not disclosed between the comparative sites at completion of the study, evidence for a shift in the phenotype of
connective tissue cells was obtained. The main retinol-related change consisted of a 2- to 5-fold increase in the
number of factor XIIIa+ dendrocytes both in the dermis and fibrous strands of the hypodermis.
Conclusions: We hypothesize that the functional and phenotypic changes seen in this study were linked and
represent the result of a direct or indirect modulating effect of retinol on cellulite. Such features ultimately
improve the resting tensions inside the skin which should in turn smooth the skin surface.

Background that cellulite follows a 2-step evolution.[3] Incipient cellulite is

Cellulite occurs to varying degrees on the thighs and buttocks
of many otherwise healthy women. The microanatomical basis of
such condition is still debated.[1-3] Some of our uncertainties re-
sult from the small number of objective scientific and comprehen-
sive studies that have been performed in this area. In addition,
persisting misconceptions and scientific prejudices contribute to
cloud many issues that are critical in allowing the real culprit in
cellulite to be tackled. The condition is essentially a gender and
body region–linked characteristic. We have provided evidence
recognized by the mattress phenomenon upon pinching the skin
and moderate fat lobule enlargement with reactive focal
fibrosclerotic hyperplasia of connective tissue strands partition-
ing the subcutis. Women who do not put on excess bodyweight
rarely develop the severe, full-blown cellulite. Such a condition
results from the presence of the equivalent of stretch marks in the
hypodermal connective tissue.[3]
Innovation in cellulite care has been stifled by unsubstanti-
ated claims for products that have for many years failed to satisfy
the expectations of consumers. In this field, the rules of a com-
370
MD3
MD1
0.2
Elevation (mm)
ED1
ER1
0.1
RD1
0 Bioinstrumental evaluations were performed at entry into the
0 5 10 15 20 25
Time (s)
Fig. 1. Recorded mechanical parameters during cyclic variations in the elevation
of skin in time. ED1 = elastic (immediate) distension of the skin during the first
traction (0.15s); MD1 = maximum distension of the skin at the end of the first
traction (5s); ER1 = elastic (immediate) retraction of the skin during the first cycle
(5.1s); RD1 = residual deformation of the skin at the end of the first cycle (10s);
MD3 = maximum deformation of the skin at the end of the third traction (25s).
petitive market were most likely a powerful confounder. As a
consequence, many purported cosmetic and medical treatments
show little effect in improving cellulite, and certainly none cause
its complete disappearance.[4-9] To advance knowledge and to
serve consumers better, the futile search for a treatment that will
cure cellulite should be put aside. The aim of treatment should be
to minimize the physical aspects of cellulite and to prevent pro-
gression into the stage of full-blown cellulite. Certainly, it has
been, and will continue to be, necessary to accept a less than the
ideal outcome from treatment for this skin condition.
We view cellulite as the result of an imbalance between mod-
erate but chronic excess in fat lobule pressure and less than perfect
reactive processes taking place in the hypodermal fibrous
strands.[3] The rationale for cellulite care at an early stage should
then be directed at 1 of 3 major areas: (i) reducing estrogen-re-
lated regional fat accumulation; (ii) using continuous external
compression therapy; or (iii) boosting and modulating the con-
nective tissue metabolism to prevent the occurrence of hypoder-
mal stretch marks. As topical tretinoin has been reported to im-
prove early dermal striae distensae,[10-12] this compound or a
similar product might also bring a similar benefit on cellulite. In
fact, retinoids including retinol (vitamin A) have already been
evaluated for their effectiveness in the treatment of cellulite.[5,7,13]
Such a background prompted us to critically explore the reputed
effect of topical retinol to alleviate the physical signs of cellulite.
© Adis International Limited. All rights reserved.
Piérard-Franchimont et al.
Materials and Methods
A randomized, placebo-controlled study was undertaken in
15 women aged from 26 to 44 years who had requested liposuc-
tion to improve mild to moderate cellulite. Ten of them only ex-
hibited the mattress phenomenon and the 5 others had a moderate
lumpy-bumpy appearance of the skin. Prior to liposuction, they
were willing to apply a stabilized retinol formulation (Retinol
Actif Pur®, Roche) for 6 months on 1 thigh on a daily basis. A
hydrating product (Neo Dermalex®, Galenco) was applied on the
other thigh. The investigators were blinded with regard to the
randomized left-right side allocation of the products.
30
study and after 3 and 6 months of topical treatment. The test areas
were located on symmetrical sites on the mid portion of the
posterolateral aspect of the thighs. They were relocated with pre-
cision at each evaluation time using a 4-point template. The mean
dermo-epidermal thickness was calculated on each test site from
5 measurements using a 20 MHz ultrasonography A mode scanner
(Dermascan A®, Cortex Technology, Haserud, Sweden).[14] The
tensile properties of skin were assessed using a suction device
(Cutometer SM474®, C + K Electronic, Cologne, Germany) equip-
ped with a hand-held probe centered by a suction head of 4mm
diameter. The time/strain mode was used with 3 cycles of 5s trac-
tion under negative pressure of 500 mbar separated by 5s relax-
ation periods. Measures were taken during the first and third cy-
cles of suction. The operating mode and rheologic parameters
were previously described in detail.[14-16] They are illustrated in
figure 1. Each cycle of suction to the skin results in an immediate
elastic distension (ED), followed by a delayed viscoelastic dis-
tension, ending with the measurement of the maximum distension
(MD) of the skin obtained after a 5s traction. When the traction
is discontinued, the skin tends to return to its initial position.
During that phase, 2 parameters are recorded, namely the imme-
diate elastic retraction (ER) and the resilient distension (RD) after
a 5s relaxation time. The differential distension (DD) is measured
as the difference in MD between the third and the first cycles. In
Table I. Rheological ratios (%) derived from the parameters depicted in
figure 1
Extension phase during skin elevation
Viscoelastic ratio (VER) = 102 (MD-ED) ED−1
Recovery phase during skin retraction
Biologic elasticity (BE) = 102 (MD-RD) MD−1
Relative elastic recovery (RER) = 102 (MD-ER) MD−1
Elastic function (EF) = 102 (MD-ER) ED−1
ED = elastic distention; ER = elastic relaxation; MD = maximum
distention; RD = resilient distention.
Am J Clin Dermatol 2000 Nov-Dec; 1 (6)
Topical Retinol for Cellulite
Table II. Panel of antibodies and lectin used to identify connective tissue
cells responding to the retinol treatment
Antibody/lectin Dilution Source Target
Anti-factor XIIIa 1 : 300 Behring Dermal dendrocytes
type I
Anti-CD34 1 : 200 Bekton Dermal dendrocytes
type II
Anti-α-actin 1 : 20 Dako Smooth muscle cells
and myofibroblasts
Ulex europaeus 1 : 80 Dako Endothelial cells
agglutinin 1
addition, certain biologically relevant ratios of these parameters
were calculated (table I).
The normality of the distribution of each variable was veri-
fied using the Wills-Shapiro test. Data were expressed as the mean
with standard deviations for all patients. Differences in the tensile
properties of skin with time at each test site were tested for their
statistical significance using variance analysis. Comparison be-
tween the 2 test sites at entry and at completion of the study were
made by the paired Student’s t-test. A p-value less than 0.05 was
considered significant.
At completion of the 6-month treatment phase, two 8mm
punch biopsies were taken 1cm beneath the crease between but-
tocks and thighs where the mattress phenomenon was present.
They corresponded to the active and placebo treated sites, respec-
tively. The specimens were subjected to histologic and immuno-
histologic assessments that are identical to those used in a previ-
ous study.[3] Sections were stained by hematoxylin-eosin, Masson’s
trichrome, orcein-giemsa, sirius red and PAS-colloidal iron.
Other sections were used for immunohistochemistry. Antibodies
used are listed in table II.
Results
Bio-Instrumental Assessments
At the end of the 6-month trial, the mean dermal thickness
remained almost unchanged at the retinol- and placebo-treated
sites (table III). Tensile properties of skin exhibiting the mattress
phenomenon were progressively modified on the thighs treated
with retinol whereas no changes were observed on the control
sites (table IV). The most salient modifications related to retinol
applications were a 10.7% increase in elasticity (biologic elastic-
ity). The relative elastic recovery followed the same trend. By
contrast, the creeping phenomenon (DD) and viscosity decreased
by 23.5% and 15.8%, respectively (fig. 2). Significant differences
were yielded after the 6 months of retinol treatment in the com-
© Adis International Limited. All rights reserved.
371
parison with both the respective baseline values and those on the
control site at completion of the study (table IV).
In the 5 women with lumpy-bumpy skin, prominent interin-
dividual differences in tensile properties of the skin at the test
sites were present. Although the trends in biomechanical changes
were almost similar to those observed at the test sites of the
women with mattress phenomenon, they did not reach statistical
significance (table V).
Microscopic Assessment
The comparative assessment of the standard histologic sec-
tions did not show evidence of prominent differences between the
retinol and placebo test sites. In contrast, phenotypic changes
were present in connective tissue cells of the retinol-treated skin.
Both the number of factor XIIIa+ dendrocytes and the ratio be-
tween these cells and CD34+ cells showed a 2- to 5-fold increase
in the dermis and hypodermal fibrous strands (fig. 3). The α-ac-
tin+ myofibroblasts were not identified at the retinol-treated site
although a few of them were scattered in some thickened portions
of hypodermal fibrous strands at the control site. In 3 women, the
microvasculature highlighted by the lectin Ulex europaeus agglu-
tinin-I was developed with better uniformity in the dermis and hypo-
dermis at the retinol-treated site. The difference in vasculature
between the 2 test sites was inconspicuous in the other women.
Discussion
Increasingly, women are seeking professional advice regard-
ing the growing stream of products and techniques that promise
to improve their cellulite. Physicians need to be informed about
the great range in efficacy among the purported treatments, if for
no other reason than to steer patients clear of untested products.
A better reason is so that physicians are able to provide guidance
on the proper use of formulations that have proven benefit.
Physical activity, bodyweight reduction, massage[7-9] and lipo-
suction[6,17] are measures that currently purport to be more effec-
tive than placebo in the cellulite care. However, reported data are
not always convincing because the studies that have been per-
Table III. Mean (± SD) of dermal thickness (mm) at retinol and placebo
treated sites evaluated by 20 Mhz ultrasonography
Evaluation Retinol Placebo
time mattress skin dimpled skin mattress dimpled skin
skin
Baseline 1.1 ± 0.2 1.0 ± 0.2 1.0 ± 0.2 1.0 ± 0.2
Month 3 1.2 ± 0.2 1.1 ± 0.3 1.1 ± 0.3 1.0 ± 0.3
Month 6 1.2 ± 0.2 1.1 ± 0.2 1.0 ± 0.1 1.0 ± 0.2
Am J Clin Dermatol 2000 Nov-Dec; 1 (6)
372 Piérard-Franchimont et al.

Table IV. Tensile properties (mean ± SD) of skin exhibiting the mattress phenomenon in 10 women
Biomechanical parameters Baseline Month 3 Month 6
retinol placebo retinol placebo retinol placebo
MD (μm) 219 ± 56 227 ± 61 223 ± 53 225 ± 58 216 ± 48 226 ± 59
DD (μm) 17 ± 5 15 ± 6 15 ± 4 17 ± 6 13 ± 4a,b 17 ± 4
VER (%) 38 ± 7 36 ± 6 36 ± 8 38 ± 9 32 ± 6a,b 39 ± 8
BE (%) 65 ± 8 67 ± 8 68 ± 9a 66 ± 6 72 ± 10c,b 66 ± 7
RER (%) 41 ± 8 40 ± 9 43 ± 7 41 ± 8 46 ± 5a,d 39 ± 9
EF (%) 53 ± 9 54 ± 10 53 ± 11 55 ± 9 55 ± 8 53 ± 7
a Significant difference with baseline values (p < 0.05).
b Significant difference with the placebo values at the same evaluation time (p < 0.05).
c Significant difference with baseline values (p < 0.01).
d Significant difference with the placebo values at the same evaluation time (p < 0.01).
BE = biologic elasticity; DD = differential distension; EF = elastic function; MD = maximum distention; RER = relative elastic recovery; VER = viscoelastic
ratio.

formed are supported by high technology but unfortunately suffer
from biased designs and flawed concepts. It is obvious that sub-
jective assessments of cellulite cannot be seen as an unambiguous
scientific tool to produce reliable knowledge. If objective meas-
urements are mandatory we disagree[3] with the contention that
the evaluation of the waviness of the dermo-hypodermal interface
as assessed by ultrasound imaging[9,18] can be used to measure the
severity of cellulite and the success of its treatments. In fact the
wavy appearance of that interface is largely a gender-linked char-
acteristic and its relationship with cellulite might be fortuitous.
There is no proven link of causality between upward position of
the fat compartments beneath the dermis and cellulite. In addi-
tion, the size of these papillae adiposae is much smaller than the
uneven bumpy aspect of the skin surface. The lack of correlation
between the extent in dermo-hypodermal waviness and the sever-
ity of cellulite also points to the irrelevance of evaluating thera-
peutic effects on cellulite through such a microanatomical
inside the connective tissue of the subcutis.[3] The lumpy-bumpy
aspect of the skin occurs, the outward protrusions corresponding
to the most altered portions of the hypodermis. We take strong
exception to the concept that inflammation or hampered lymph
and blood circulations[8,19] play prominent or pathogenic roles in
the development of cellulite.
The present controlled 6-month study suggests some changes
mediated by retinol at the functional and phenotypic levels of the
dermis and subcutis. Such modulatory effects were present before
any demonstrable remodelling of these tissues. One might ques-
tion the relevance of those findings for the consumer. In fact, the
Retinol
Placebo
15
** *
10
5
Variation (%)

presentation.[3] In fact, it is astonishing to us that regular electro-

0
mechanical massage might affect the gender-related charac-
teristic of the dermo-hypodermal interface as has been previously −5

reported.[9] The relevance of such finding remains elusive. −10

In our experience, the cellulite-prone condition is due to −15
moderate increase in fat deposits within clustered hypodermal *
−20
lobules encased by focally thickened and fibrosclerotic strands
containing a few myofibroblasts.[3] As such clusters of fat lobules −25
*
DD VER BE RER
are not compressible, but can change in shape, they are squeezed
upward upon pinching the skin while their fibrosclerotic strands
acts like belts and shrouds bound to the deepest fascia. The mat- Fig. 2. Percentage variation in rheologic parameters significantly (*p<0.05,
tress phenomenon is the result of such fat outpouching restricted **p<0.01) influenced by the retinol treatment at the site of the mattress phenome-
non. Comparisons are made at both retinol and placebo (%) test sites between
by a tethering fibrosclerotic network. In time and with further
values yielded after the 6-month treatments and baseline. The changes are indic-
accumulation of fat, intrahypodermal pressure increases pushing ative of increased skin firmness. BE = biologic elasticity; DD = differential disten-
the fibrous strands under excessive tension. Stretch marks ensue sion; RER = relative elastic recovery; VER = viscoelastic ratio.

© Adis International Limited. All rights reserved. Am J Clin Dermatol 2000 Nov-Dec; 1 (6)
Topical Retinol for Cellulite 373

Table V. Tensile properties (mean ± SD) of lumpy-bumpy sites in 5 women

Biomechanical parameters Baseline Month 3 Month 6
retinol placebo retinol placebo retinol placebo
MD (μm) 198 ± 78 189 ± 84 204 ± 69 192 ± 79 193 ± 76 195 ± 88
DD (μm) 19 ± 9 18 ± 8 18 ± 8 19 ± 9 16 ± 7 18 ± 7
VER (%) 42 ± 9 41 ± 9 41 ± 7 41 ± 8 38 ± 7 40 ± 10
BE (%) 63 ± 9 65 ± 10 65 ± 9 64 ± 10 67 ± 8 64 ± 9
RER (%) 39 ± 8 39 ± 9 38 ± 9 39 ± 10 41 ± 7 38 ± 10
EF (%) 51 ± 10 53 ± 12 52 ± 9 53 ± 10 52 ± 8 53 ± 9
BE = biologic elasticity; DD = differential distension; EF = elastic function; MD = maximum distention; RER = relative elastic recovery; VER = viscoelastic
ratio.

present information provides a framework for exploring a bio- The clearest lesson to take away from the present study is
logic way to alleviate cellulite. It does not solve the whole stub- that topical retinol treatment may improve the tensile properties
born enigma around this skin condition. However, our findings of skin in a beneficial way for cellulite care. This aspect is corre-
are largely congruent with those reported by another group.[13] lated with, and might be due to, a shift in the phenotypic differ-
Skin is a complex composite of tissues whose functions de- entiation of connective tissue cells. Although no one could argue
pend on the mutual interdependence of its constituent parts. By that retinol is a panacea, it represents a reasonable, affordable
using the biomechanical methods described, the overall tensile biologic modifier whose effects may help reduce the severity of
properties that were evaluated represented, in part, the attributes cellulite. From these results, it appears that the earlier treatment
of the dermal and hypodermal structures.[15,17,20] The increase in is started, the greater benefit could be expected. This has already
elasticity combined with a decreased viscosity at the retinol- been shown for dermal striae distensae.[10-12,38] Extrapolating
treated site were, however, not supported by significant changes from this one might speculate that retinol and products with
in dermal thickness or by recognisable clues in the gross retinoid-like effects will yield their best effects in cellulite when
microanatomy of the tissues. Hence, we frame as a hypothesis used as a preventive measure. One might also consider specific
that the biomechanical changes were related to a difference in
uses where retinol is applied to the affected area, and covered with
resting tensions inside the skin. In fact, the increased elasticity
a compressive bandage or garment to combine the beneficial ef-
and decreased viscosity should be interpreted as beneficial be-
fects of compression and enhanced penetration of retinol.
cause such changes would allow a better uniform repartition of
forces inside the subcutis with less risk for hypodermal stretch
marks. Such an effect should ultimately smooth the skin surface
and decrease the mattress phenomenon and skin dimpling.
The intimate mechanical interactions between connective
tissue cells and their extracellular matrix are notoriously com-
plex. Phenotypic changes occur both as a cause and as a conse-
quence of intratissular tensions.[21-23] Retinoids also target dermal
cells and may affect the synthesis-degradation balance of the ma-
trix macromolecules.[24-31] Previous observations[32] and the pres-
ent findings concur to the concept that retinol among retinoids
boost factor XIIIa immunoreactivity in dendrocytes. Other works
have indicated that factor XIIIa is important in the control of
collagen synthesis and degradation, and in overall connective tis-
sue biology and structure.[23,33-35] Whether or not such a pheno-
typic change is the cornerstone of the operating mode leading to
the improvement in the tensile properties of skin remains to be
settled. It was, however, already suggested in previous stud- Fig. 3. Numerous and large factor XIIIa+ dendrocytes in the deep dermis after
ies.[36,37] 6-months’ treatment with retinol.

© Adis International Limited. All rights reserved. Am J Clin Dermatol 2000 Nov-Dec; 1 (6)
374
Conclusion
This randomized, placebo-controlled study indicates that
topical retinol combined with gentle massage influences the phe-
notypic presentation of some dermal cells and modifies the tensile
strength of the skin. The rheologic changes are indicative of in-
creased skin firmness. Such features should, in turn, smooth the
skin surface of incipient cellulite.
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Correspondence and offprints: Dr Gérald E. Piérard, Department of
Dermatopathology, CHU Sart Tilman, B-4000 Liège, Belgium.
Am J Clin Dermatol 2000 Nov-Dec; 1 (6)