Dermatologic Therapy, Vol. 19, 2006, 289 –296 Copyright © Blackwell Publishing, Inc.

, 2006
Printed in the United States · All rights reserved
DERMATOLOGIC THERAPY
ISSN 1396-0296

Retinoids in cosmeceuticals
Blackwell Publishing Inc

OLIVIER SORG, CHRISTOPHE ANTILLE, GÜRKAN KAYA, & JEAN-HILAIRE SAURAT

Geneva University Hospital, Geneva, Switzerland

ABSTRACT: Retinoids are natural and synthetic vitamin A derivatives. They are lipophilic molecules
and easily penetrate the epidermis. Their biologically active forms can modulate the expression of
genes involved in cellular differentiation and proliferation. Retinoic acid (tretinoin), its 13-cis isomer
isotretinoin, as well as various synthetic retinoids are used for therapeutic purposes, whereas reti-
naldehyde, retinol, and retinyl esters, because of their controlled conversion to retinoic acid or their
direct receptor-independent biologic action, can be used as cosmeceuticals. These natural retinoic
acid precursors are thus expected to be helpful in (i) renewing epidermal cells, (ii) acting as UV filters,
(iii) preventing oxidative stress, (iv) controlling cutaneous bacterial flora, and (v) improving skin
aging and photoaging. Retinol and retinyl esters are not irritant, whereas demonstrating only a
modest clinical efficiency. On the other hand, retinaldehyde, which is fairly well tolerated, seems to
be the most efficient cosmeceutical retinoid; it has significant efficiency toward oxidative stress, cuta-
neous bacterial flora, epidermis renewing, and photoaging.

KEYWORDS: cosmeceutical, photoaging, photoprotection, retinoids

Topical retinoids as “cosmeceuticals” ligand-receptor complexes modulate the expression

The scope of topical cosmeceutical retinoids
The rather ill-defined word cosmeceutical may
be understood as one applicable to a natural
compound, which is not a drug but still exerts
demonstrable biologic activity without inducing
side effects. In the field of topical retinoids, this
would exclude retinoic acid because it is registered
as a drug, and all synthetic retinoids such as ada-
palene, tazarotene, and bexarotene. The eligible
candidates in the group of topical cosmeceutical
retinoids are: retinyl esters, retinol, retinaldehyde,
and the group of oxoretinoids.
Endogenous cutaneous natural retinoids
Retinoids define a class of substances comprising
vitamin A (retinol) and its natural and synthetic
derivatives. As lipophilic molecules, they can
diffuse through cellular and other phospholipid
membranes. Inside the cells, they bind to nuclear
receptors (RAR-α, -β, -γ, and RXR-α, -β, -γ) then the
Address correspondence and reprint requests to: Olivier Sorg,
Ph.D, Clinique de Dermatologie, Hôpital Cantonal Universi-
taire, 24 rue Micheli-du-Crest, 1211 Genève 14 (Switzerland), or
email: olivier.sorg@hcuge.ch.
of genes involved in cellular differentiation and
proliferation (1–3). Retinol is produced in the
small intestine either by hydrolysis of retinyl
esters, or by oxidation of various carotenoids (4 –6).
Retinol can be oxidized into retinaldehyde, and
then into retinoic acid, the biologically active form
of vitamin A (FIG. 1). On the other hand, retinol
can be esterified with fatty acids to form retinyl
esters (2,7,8). In the blood and tissues, the two
predominant endogenous retinoids are retinol
and its esters. Retinoids are present in the skin:
retinol and retinyl esters account for more than
99% of total cutaneous retinoids, i.e., approxi-
mately 1 nmol/g, whereas retinaldehyde and
retinoic acid are under the limit of detection
(10 pmol/g) (9–11). Retinoic acid is catabolized
either by phase I or phase II enzymes, giving rise
to retinoyl glucuronide or 4-oxoretinoic acid
(12,13).
Biologic evidence for the use of topical
cosmeceutical retinoids
Although primarily an esthetic problem with sig-
nificant psychologic effects, intrinsic and extrinsic
skin aging constitutes the background for the

289
Sorg et al.
FIG. 1. Structure of natural retinoids. The arrows show the enzyme-catalyzed conversions. The dotted-lined arrows are
probable conversions, although they have not been confirmed.
development of precancerous and cancerous
skin lesions. Many clinical studies indicate that
certain structural changes induced by excessive
sun exposure can be reversed, to some extent, by
the use of topical retinoids (14). Retinoic acid is
widely used both for topical therapy of several
skin diseases and to improve the aspect of aging
skin. However, topical retinoic acid induces irrita-
tion of the skin, which precludes its use in some
skin diseases that respond to systemic retinoids.
Irritation might be explained, at least in part, by
an overload of the retinoic acid-dependent path-
ways with nonphysiologic amounts of exogenous
retinoic acid in the skin. It is still not established
whether all the therapeutic activities of topical
retinoic acid are mediated by nuclear receptors,
and whether irritation is necessary for obtaining
some of these activities. To overcome the prob-
lems encountered by retinoic acid, one possibility
is that significant biologic activity may still be
achieved with much lower concentrations of topical
retinoic acid; in this case, retinoic acid is delivered
at a low rate from a large epidermal reservoir, i.e.,
the stratum corneum, to its intracellular targets.
Topical cosmeceutical retinoids would reproduce
the different activities of retinoic acid, but through
different pathways, which would explain better
tolerability, albeit apparently lower biologic activity
(Table 1).
Delivery of ligand for retinoic acid receptor
(RAR) binding corresponds to the genomic effects
of topical cosmeceutical retinoids, and many
other, either proved or putative biologic activities
would account for other effects. This introduces
the notion of a specific profile of clinical potential
for each of the topical cosmeceutical retinoids.
290
The intracrine-proligand concept as a basis for
the genomic effects of cosmeceutical topical
retinoids
Instead of treating the skin with natural or syn-
thetic ligands of nuclear receptors (that are poten-
tially more toxic because they deliver preformed
pharmacologic activity, thus their classification
as drugs), delivery could be distinctly targeted
with proligand, molecules that the target cell will
transform in a controlled process into active
ligands (15). This intracrine concept, in which the
active ligand is produced within the targets cells,
has been explored to deliver retinoid activity to
mouse and human skin topically with natural
retinoids that do not bind to nuclear receptors
(9,16–20). This might be one definition of cosme-
ceutical topical retinoids.
Experimental evidence
Validation of the concept implies that (i) epider-
mal cells metabolize the precursors into retinoic
Table 1. Topical retinoids: effects relevant for
anti-aging for activity
Epidermal cells renewal
Epidermal differentiation modulation
Extracellular matrix production
Inhibition of UV-induced extracellular matrix
degradation
Cytokine modulation – angiogenesis
Melanocyte function modulation
Oxidant/antioxidant
Prevention of UV-induced vitamin A deficiency
Sunscreen effect
So-called surface effects

acid or another biologically active retinoid, (ii)
topical application of the precursor results in bio-
logic effects, and (iii) tolerability of the precursor is
better than that of the active metabolite (9,21–25).
The ranking order of retinoid-like activity follow-
ing topical application is as follows: retinoic acid >
retinaldehyde > retinol > > retinyl esters; in other
words, this corresponds to the metabolic pathway
(the closer to retinoic acid, the higher retinoid-
like activity they have): retinyl esters are hydro-
lyzed to retinol, which is oxidized to retinal, which
is in turn oxidized to retinoic acid. On the other
hand, probably for the same reason, the tolerance
ranking order is the opposite: retinyl esters >
retinol = retinaldehyde > > retinoic acid.
The genomic effects of topical retinoids most
probably account for inducing many of the bio-
logic effects involved in reversing and preventing
extrinsic and intrinsic skin aging such as the pre-
vention of matrix metalloproteinase activation
(26,27) and oxidative stress and the regeneration
of extracellular matrix (28) (Table 1).
In particular, retinoids are known to inhibit
keratinocyte differentiation and to stimulate epi-
dermal hyperplasia. Heparin binding-epidermal
growth factor (HB-EGF) activation of keratinocyte
ErbB receptors via a RAR-dependent paracrine
loop has been proposed to mediate retinoid-
induced epidermal hyperplasia (29). It has been
shown that CD44v3, a heparan sulfate-bearing
variant of CD44 which is a multifunctional poly-
morphic proteoglycan and principal cell surface
receptor of hyaluronate, recruits proteolytically
active matrix metalloproteinase 7, the precursor
of HB-EGF (pro-HB-EGF) and one of its receptors,
ErbB4, to form a complex on the surface of
murine epithelial cells (30). The present authors
have previously shown that topical application of
retinaldehyde increases the expression of CD44 in
mouse skin. The increased expression of CD44
accompanying epidermal hyperplasia induced by
topically applied retinaldehyde is associated with
an increase in epidermal and dermal hyaluronate
and with increased expression of hyaluronate-
polymerizing enzymes, hyaluronate synthases 1, 2,
and 3 (31). The observations of the present authors
indicate that the hyaluronate system might be
associated with the heparin-binding epidermal
growth factor (HB-EGF) paracrine loop, with the
transcriptional up-regulation of CD44 and hyalur-
onate synthases. The present authors have also
shown that retinaldehyde-induced in vitro and in
vivo proliferative response of keratinocytes is a CD44-
dependent phenomenon requiring the presence
of HB-EGF, another HB-EGF receptor, ErbB1, and
Retinoids in cosmeceuticals
matrix metalloproteinases (32). The integration
of the retinoid-induced CD44, hyaluronate, and
HB-EGF modulation in the biologic effects of
topical retinoids now requires further studies.
Clinical evidence and implications
There are now many evidence-based clinical
observations establishing the effects of topical
cosmeceutical retinoids in this context (33).
The first study on the effect of tretinoin on the
wrinkles of the face was published in 1983 (34). In
this small, vehicle-controlled study, tretinoin,
used at a concentration range of 0.001–0.05%, has
been shown to produce a mild to moderate
improvement in wrinkles at 6 months and in
actinic lentigines at 4 months. In an open study,
tretinoin 0.05% cream was used for 3–10 months
on photoaged skin of the face and forearm and
a clinical improvement was observed (35). In a
4-month randomized vehicle-controlled trial, it
was shown that 0.1% tretinoin cream used once
daily could significantly improve the fine facial
wrinkling as a result of chronic sun exposure
(36).
Although there is extensive literature on the use
of topical tretinoin for the treatment of photoaged
skin, few studies have been reported for other ret-
inoids. In a 36-week study of once-daily isotretin-
oin 0.1% cream, it was shown that isotretinoin
was effective in the treatment of coarse and fine
wrinkles and actinic lentigines (37). When com-
pared to tretinoin, isotretinoin appears to be less
irritating and maybe less effective. In two other
studies, a clinical improvement has been shown
in fine wrinkles after 36 weeks of treatment with
isotretinoin 0.05% and 0.1% cream (38,39). The
efficacy of retinaldehyde 0.05% cream for treat-
ment of photoaging has been compared with
0.05% tretinoin and vehicle creams during 18
weeks (40). Retinaldehyde produces significant
clinical improvement in fine and deep wrinkles,
which was maintained during 44 weeks. The posi-
tive effect of retinaldehyde on wrinkles has been
confirmed by a second study (41). Retinaldehyde
seems to be significantly less irritant than tretin-
oin. In a randomized, controlled trial it was
reported that a retinol-containing formulation
resulted in significant improvement in fine wrin-
kles after 12 weeks of treatment (42). Retinol 0.4%
has been shown to induce a similar epidermal
hyperplasia in human skin as tretinoin 0.1% but
with significantly less irritancy (16) (Kaya et al.,
unpublished data). In contrast, topical retinyl
propionate cream (0.15%) is not effective in the
treatment of photoaged skin (43).
291
Sorg et al.
Nongenomic effects of topical cosmeceutical
retinoids
Retinoids might exert a biologic activity indepen-
dently of their binding to nuclear receptors. These
effects are probably differently exerted by retinyl
esters, retinol, retinaldehyde, and retinoic acid,
which introduce a further level of choice for the
clinician amongst cosmeceutical topical retinoids.
Some of these effects have been well demon-
strated experimentally, and some evidence of
their clinical application already obtained.
The paradoxical UV filter properties
Experimental evidence: Besides their biologic
action mediated by nuclear receptors, because of
their side chain containing conjugated double
bonds, retinoids strongly absorb ultraviolet (UV)
light, and thus appear as potential UV filters.
To assess the relevance of this concept, the present
authors first developed an in vitro model in which
liposomes, the membranes of which are enriched
in a lipophilic putative UV filter, are encapsulated
with a fluorescent probe; this model appears
suitable to easily analyze the filtering capacities
of new molecules within a simulated biologic
environment.
In a series of experiment in mice, the present
authors demonstrated that natural retinoids
(retinoic acid, retinaldehyde, retinol, and retinyl
palmitate) were efficient in preventing UVB-induced
apoptosis and DNA photodamage (44). The similar
potencies of these retinoids indicate a physical
action mediated by their spectral properties
rather than a biologic action mediated by the
binding to nuclear receptors.
In a human study, the photoprotective action
of topical retinyl palmitate 2% was shown to be as
efficient as that of a sunscreen with a sun protec-
tion factor of 20 in preventing UVB-induced
erythema and DNA photodamage (45).
Clinical evidence and implication: Although the
risk incurred when exposing the skin to the sun
following topical retinoids is still a matter of
debate, it is important to underline that human
studies showed prevention or no effect of topical
retinoids on nonmelanoma skin cancers (46–50).
The studies reporting a potentiation by retinoids
of UV-induced skin diseases are based on studies
performed in vitro or in animal models (51–54).
The antibacterial activity of retinaldehyde
Experimental evidence: Aldehydes represent a a lack of clinical evidence regarding the efficiency
class of highly reactive compounds, especially
292
toward alcohols and amines; retinaldehyde may
thus exert a direct activity by reacting nonenzy-
matically with many biologic molecules on skin
surface, as well as on bacterial flora, independent
of its conversion to retinoic acid and subsequent
activation of nuclear receptors (55–59).
Clinical evidence and implication: Although vita-
min A was recognized as a putative anti-infective
agent as early as in the 1920s (60), its mechanism
of action still remains elusive. Retinoic acid has
been shown to protect dendritic cells in mice (61)
and topical retinaldehyde, owing to its better tol-
erance profile than retinoic acid, was successfully
applied for a long period of time to patients with
inflammatory dermatoses (23). More recent stud-
ies demonstrated a higher antibacterial profile of
retinaldehyde and nonretinoid aldehydes than
retinoic acid on several bacterial strains in vitro,
as well as a good antibacterial action of topical
retinaldehyde 0.05% in vivo (Propionibacterium
acnes and Staphylococcus spp.) (58,59).
Topical cosmeceutical retinoids as antioxidants
Oxidative stress has been shown to be the corner-
stone of the biochemical pathways leading to
photoaging (3,62–65). Although the skin, like the
other organs, possesses an efficient antioxidant
system, the latter is able to counteract the delete-
rious effects of occasional oxidative stress of
moderate magnitude, but in the case of chronic or
severe oxidative stress, it reaches its limit and irre-
mediable tissue damage is unavoidable (66–70).
On the other hand, the endogenous antioxidant
systems become less efficient in the elderly (71–74).
There is thus a need for topical antioxidants to
scavenge the remaining reactive oxygen species
and free radicals when endogenous antioxidants
are saturated.
Experimental evidence: Retinoids have been
shown to exert a free radical scavenging activity in
vitro (75–79). In hairless mice, topical menadione
(vitamin K3) induced the peroxidation of epidermal
lipids in hairless mice; this effect was completely
prevented by pretreatment with either 0.25%
topical α-tocopherol (vitamin E, a known efficient
endogenous cutaneous antioxidant) or topical
retinaldehyde 0.05% (78).
Clinical evidence and implication: Although peo-
ple with a low serum retinol are at higher risk to
develop various forms of cancers (80,81), there is
of topical natural retinoids as antioxidants.

Topical cosmeceutical retinoids and pigmentation
Topical retinoic acid has been used for many years,
alone or in combination with hydroquinone, for
the depigmentation of human skin (82,83).
Experimental evidence: The present authors used
the model of mouse tail to compare the efficiency of
topical retinaldehyde 0.05% and 4-oxoretinaldehyde
0.05% (see succeeding discussions) to decrease
epidermal pigmentation. Following a 3-week
treatment of daily application, topical retinalde-
hyde and 4-oxoretinaldehyde decreased epidermal
melanin by 80% and 54%, respectively (Sorg and
collaborators, manuscript in preparation).
Clinical evidence and implication: According to
the previously mentioned discussion on the
biologic actions of retinol, a much higher concen-
tration would be required to replace topical
tretinoin by retinol to produce similar results. In
the formula of Kligman and Willis, tretinoin 0.1%
accelerates the loss of epidermal melanin, hydro-
quinone 5% suppresses its production, whereas
dexamethasone 0.1% prevents the irritant derma-
titis induced by tretinoin (82). A clinical trial in
which retinol 10% and lactic acid 7% replaced
tretinoin 0.1% and dexamethasone 0.1% in the
formula of Kligman and Willis was successfully
applied to patients with hyperpigmented lesions
on the face (84). This new formula was shown to
be comparable to that of Kligman and Willis, with
the advantage of preventing the steroid-induced
skin atrophy (84).
Oxoretinoids
As mentioned previously, the biologic effects of
retinoids are believed to be mediated by their
interaction with the nuclear receptors RARs and
retinoid X receptors (RXRs). The known endoge-
nous ligand for RARs is retinoic acid, whereas its
9-cis isomer (9-cis-RA) activates both RARs and
RXRs (85,86). 4-Oxoretinoic acid (FIG. 1), the product
of the action of CYP26, a phase I enzyme, on retinoic
acid, was considered an inactive catabolite of
retinoic acid. However, two other 4-oxoretinoids,
i.e., 4-oxoretinol and 4-oxoretinaldehyde (FIG. 1),
have been shown to exert direct retinoid-like
activity in vitro, which suggests a potential benefit
for their use as cosmeceuticals (87–92).
Experimental evidence: In a mouse model, topi-
cal 4-oxoretinaldehyde 0.05% induced a moderate
retinoid-like activity compared to topical retinoic
acid 0.05%, as assessed by (i) epidermal hyperpla-
sia and metaplasia, (ii) cutaneous inflammation
Retinoids in cosmeceuticals
(myeloperoxidase activity), and (iii) depigmentation
of the tail (Sorg and collaborators, manuscript in
preparation). In this model, topical 4-oxoretinol
0.05% demonstrated a lower biologic activity. Par-
allel to the action of 4-oxoretinoids, no retinoic
acid could be detected in the skin, indicating that
4-oxoretinoids exerted a direct biologic activity,
which was not the result of the conversion of 4-
oxoretinoids to their non-oxo counterparts. These
results thus confirm in vitro studies demonstrating
that 4-oxoretinol and 4-oxoretinaldehyde are capable
of binding to and transactivating RARs (87,89).
Clinical evidence and implication: No clinical trial
using topical 4-oxoretinoids has been reported so
far. However, the mentioned data on the biologic
activity of 4-oxoretinaldehyde, and to a lesser
extent 4-oxoretinol, let us imagine potential bene-
fits of these new natural vitamin A derivatives.
Future trials are needed to determine whether it is
possible to use these retinoids at high concentra-
tions with better response than tretinoin and with
acceptable side effects.
The specific profile of clinical potential
for each of the topical cosmeceutical
retinoids
Retinaldehyde
Retinaldehyde, the precursor of retinoic acid (FIG. 1),
is much less irritant than retinoic acid. Retinaldehyde
has been shown to be well tolerated and effective
in treating photoaging: in particular, retinaldehyde
produced significant improvement in fine and
deep wrinkles, whereas side effects of topical retinoic
acid affected compliance of the patients (23,41).
Retinaldehyde does not bind to nuclear retinoid
receptors and selectively delivers low concentra-
tions of retinoic acid (22,93); this prevents an
excess of retinoic acid in the skin, a condition that
contributes to cutaneous irritation (9,15) and confers
to retinaldehyde the required properties for the
intracrine concept (15). This concept has been
expanded in a recent study on ex vivo human skin
by combining retinaldehyde and a vitamin E
precursor (tocopheryl glucose): this improved the
protection against the generation of free radicals –
a condition leading to aging – as well as the skin
elasticity (94).
Because of its aldehyde functional group, reti-
naldehyde exerts direct receptor-independent
biologic actions not shared by other retinoids. This
293
Sorg et al.
explains the usefulness of topical retinaldehyde
0.05% against P. acnes and Staphylococcus spp. (58,59).
As mentioned above, retinoids strongly absorb
in the UV range and thus appear as putative filters
when applied to the skin. Retinaldehyde absorbs
in the UVA-visible range (λmax = 385 nm) and may
decrease the fluence received in this window sig-
nificantly. This concept has been illustrated in the
present authors’ recent study reporting a similar
filter effect of the various topical natural retinoids
0.05% (retinyl palmitate, retinol, retinaldehyde
and retinoic acid) on UV-induced apoptosis and
DNA photodamage in mice (44).
Retinaldehyde is also the most efficient topical
retinoid to load the skin with retinol and its esters
– the storage form of cutaneous vitamin A
(9,19,20,95,96). The organism does not store reti-
naldehyde, although it is the first retinoid pro-
duced from carotenoids in the small intestine
(5,97,98). Thus, topical retinaldehyde is rapidly
metabolized: it is mostly converted by epidermal
cells to retinol and retinyl esters, and a smaller
part is oxidized to retinoic acid (98–101).
Retinol and retinyl esters
Retinol has been incorporated into many skin
products. Theoretically, topical retinol, a precursor
of cutaneous retinaldehyde and retinoic acid,
could also be useful in treating skin conditions for
which retinaldehyde and retinoic acid are active.
However, although retinol is widely used in cosmetic
formulations to improve photoaging, topical retinol
has not been demonstrated to be effective to treat
any skin condition, maybe because of its slow oxi-
dation into retinaldehyde and retinoic acid (102).
This is confirmed by in vivo studies where topical
retinol was shown to have a modest retinoid-like
biologic activity compared to those of topical reti-
naldehyde and retinoic acid. For instance, topical
retinol application on normal human skin was shown
to induce epidermal thickening and to enhance
the expression of cellular retinoic acid-binding
protein II and cellular retinol-binding protein to a
much lower extent than retinoic acid (24,103).
Retinol absorbs UV light in shorter wavelengths
(325 nm) than retinaldehyde (385 nm) and retinoic
acid (345 nm), is less irritant than the latter retin-
oids, and is a weak retinoic acid precursor. There-
fore, topical retinol could be useful as a filter in
the most biologically active solar UV range (290–
320 nm), whereas delivering small amounts of ret-
inoic acid on a relatively long period of time. This
can be expanded to retinyl esters, which have the
same UV spectrum as retinol, have the better
294
tolerance profile among topical retinoids, whereas
being the weaker retinoic acid precursors (17).
This concept has been illustrated in the mentioned
study on UV-induced apoptosis and DNA damage
(44), as well as in another study reporting a com-
parable photoprotective action of topical retinyl
palmitate 2% and a commercial sunscreen with
a sun protection factor of 20 on UVB-induced
erythema and DNA damage (45).
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