Exp Dermatol. 2010 Sep;19(9):813-20. Epub 2010 Jul 2.
Azelaic acid modulates the inflammatory response in normal
human keratinocytes through PPARgamma activation.
Mastrofrancesco A, Ottaviani M, Aspite N, Cardinali G, Izzo E, Graupe K, Zouboulis
CC, Camera E, Picardo M.
Laboratorio di Fisiopatologia Cutanea e Centro Integrato di Metabolomica, San
Gallicano Dermatologic Institute IRCCS, Rome, Italy.
Abstract
Azelaic acid (AzA), a nine-carbon dicarboxylic acid, is an agent for the topical treatment of acne.
It has also been shown to be effective in rosacea; however, the mechanism of action has not
been clarified. Because inflammation is a common feature of both conditions, we investigated
the effects of azelaic acid on the inflammatory response of normal human keratinocytes to
ultraviolet B light, which is a photosensitizer agent in rosacea. AzA, at 20 mM, a concentration
achievable following topical application of a 15% gel, suppresses ultraviolet B light-induced
interleukins-1beta, -6 and tumor necrosis factor-alpha mRNA expression and protein secretion.
Mechanistically, azelaic acid significantly reduced the ultraviolet B light-induced nuclear
translocation of nuclear factor kB p65 subunit and the phosphorylation of the p38 mitogen and
stress-activated protein kinase. Moreover, as peroxisome proliferators-activated receptor
gamma, (PPARgamma) which has a crucial role in the control of inflammation, is activated by
fatty acids and products of lipid peroxidation, we further investigated the effect of azelaic acid on
the expression of this nuclear receptor. AzA induced peroxisome proliferators-activated
receptor-gamma mRNA and its transcriptional activity. The PPARgamma antagonist GW9662
abrogated the inhibitory effects of AzA on the UVB-induced pro-inflammatory cytokines release
and on the cell proliferation. Our study provides new insights into the molecular mechanisms of
the activity of azelaic acid and lands additional evidences for its therapeutic effects on
inflammatory skin diseases, such as rosacea.
PMID: 20545756 [PubMed - indexed for MEDLINE]
Dermatol Ther. 2007 Sep-Oct;20(5):308-13.
Skin lightening preparations and the
hydroquinone controversy.
Draelos ZD.
Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
zdraelos@northstate.net
Abstract
Skin lightening preparations are widely used in dermatology by persons of all Fitzpatrick skin types. Fitzpatrick skin
types I-III require local pigment lightening for the treatment of hormonally induced melasma and postinflammatory
hyperpigmentation caused by acne and trauma. Fitzpatrick skin types IV and darker have an even greater need for
skin lightening for social reasons, as well as pigmentary changes that occur around the eyes, in the intertriginous
areas, following dermatitis, or with acne and trauma. The gold standard dermatologic agent for skin lightening was
hydroquinone, until regulatory agencies in Japan, Europe, and most recently in the United States questioned the
safety of this substance. This has encouraged research into alternative agents to inhibit skin pigmentation such as
retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N-acetyl
glucosamine. The efficacy and safety of each of these ingredients is examined as possible topical alternatives to
hydroquinone.
PMID: 18045355 [PubMed - indexed for MEDLINE]
Cutis. 2006 Feb;77(2 Suppl):22-4.
The use of topical azelaic acid for common skin
disorders other than inflammatory rosacea.
Del Rosso JQ.
University of Nevada School of Medicine, Las Vegas, USA.
Abstract
Topical azelaic acid (AzA) is approved for the treatment of acne vulgaris and inflammatory (papulopustular) rosacea.
Because of diverse mechanisms of action that correlate with potential therapeutic benefit, AzA has been used to treat
several common dermatoses including acne vulgaris, inflammatory rosacea, erythematotelangiectatic rosacea,
perioral dermatitis, melasma, and postinflammatory hyperpigmentation. This article reviews the therapeutic use of
topical AzA for the treatment of common skin disorders other than the US Food and Drug Administration (FDA)approved indications of acne vulgaris and inflammatory rosacea.
PMID: 16566285 [PubMed - indexed for MEDLINE]
J Clin Aesthet Dermatol. 2009 Jan;2(1):26-30.
Rosacea, reactive oxygen species, and azelaic Acid.
Jones DA.
Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract
Rosacea is a common skin condition thought to be primarily an inflammatory disorder. Neutrophils, in particular, have
been implicated in the inflammation associated with rosacea and mediate many of their effects through the release of
reactive oxygen species. Recently, the role of reactive oxygen species in the pathophysiology of rosacea has been
recognized. Many effective agents for rosacea, including topical azelaic acid and topical metronidazole, have antiinflammatory properties. in-vitro models have demonstrated the potent antioxidant effects of azelaic acid,
providing a potential mechanistic explanation for its efficacy in the treatment of rosacea
Photochem Photobiol Sci. 2010 Apr;9(4):578-85.
Photoprotective effects of nicotinamide.
Damian DL.
Dermatology, Gloucester House Level 3, University of Sydney at Royal Prince Alfred Hospital Camperdown, NSW,
2050, Australia. diona.damian@sswahs.nsw.gov.au
Abstract
Sun protective measures can reduce numbers of both precancerous actinic keratoses and cutaneous squamous cell
carcinomas within relatively short periods of time even in high-risk populations. Sunscreens, which tend to provide
greater protection against shortwave UVB than against longer wavelength UVA radiation, can however provide only
partial protection from the mutagenic and immune suppressive effects of sunlight. In large part, this reflects poor
compliance with proper sunscreen application and reapplication. Skin cancer is by far the most common malignancy
in Caucasian populations, and additional strategies to reduce the morbidity and economic burden of this disease are
now urgently needed. Nicotinamide, the amide form of vitamin B3, is an inexpensive agent which is used for a variety
of dermatological applications with little or no toxicity even at high doses. Nicotinamide has photoprotective
effects against carcinogenesis and immune suppression in mice, and is photoimmunoprotective in humans
when used as a lotion or orally. UV irradiation depletes keratinocytes of cellular energy and nicotinamide, which is
a precursor of nicotinamide adenine dinucleotide, may act at least in part by providing energy repletion to irradiated
cells.
PMID: 20354654 [PubMed - indexed for MEDLINE]
Int J Mol Med. 2010 Feb;25(2):249-53.
Visualization of the melanosome transfer-inhibition in a mouse
epidermal cell co-culture model.
Kim HJ, Kazi JU, Lee YR, Nguyen DH, Lee HB, Shin JH, Soh JW, Kim EK.
Department of Biological Engineering, National Research Laboratory of Skin-bioactive Material, Inha University, Incheon 402-751, Korea.
Abstract
Transfer of melanin-containing melanosomes from melanocytes to neighboring keratinocytes results in skin pigmentation. To provide a more
practical method of visualizing melanosomes in melanocytes as well as in keratinocytes, we attempted to use murine cell lines instead of
human primary cells. We generated various fluorescent fusion proteins of tyrosinase, a melanin synthesis enzyme located in the
melanosome, by using green fluorescent protein and red fluorescent protein. The intracellular localization of tyrosinase was then examined
by fluorescence and confocal microscopy. Co-culture of murine melanocytes and keratinocytes was optimized and
melanosome transfer was either stimulated with alphaMSH or partially inhibited by niacinamide. To the best of
our knowledge, this is the first study showing that a murine co-culture model, in addition to human primary cell co- culture, can be a good
tool for depigmenting agent screening by monitoring melanosome transfer.
PMID: 20043134 [PubMed - indexed for MEDLINE]
Int J Dermatol. 1991 Dec;30(12):893-5.
The treatment of melasma. 20% azelaic acid versus 4% hydroquinone
cream.
Baliña LM, Graupe K.
Source
Department of Dermatology, Argerich Hospital, Buenos Aires, Argentina.
Abstract
The efficacy of 20% azelaic acid cream and 4% hydroquinone cream, both used in conjunction with a broad-spectrum
sunscreen, against melasma was investigated in a 24-week, double-blind study with 329 women. Over the treatment
period the azelaic acid cream yielded 65% good or excellent results; no significant treatment differences were observed
with regard to overall rating, reduction in lesion size, and pigmentary intensity. Severe side effects such as allergic
sensitization or exogenous ochronosis were not observed with azelaic acid.
PMID: 1816137 [PubMed - indexed for MEDLINE]
Evidence-based topical
skin rejuvenation
Alexander A. Navarini
1,*
, Ximena Calvo
1,*
1
and Inja Bogdan Allemann
1
Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
•these authors have contributed equally to this study, Corresponding
author: alexander.navarini@usz.ch
Introduction:
A large choice of agents with preventive or rejuvenating effects is available.
However, which ones should be chosen and recommended to our patients? The
published clinical studies on the effect of topical agents in the reduction of
facial wrinkles in vivo lack accepted measuring standards and defined
endpoints.
As a clinical indicator of efficacy, we noted the maximal clinical effect on
facial wrinkles of each compound, together with the duration and type of each
study. In addition, we compared the extent of epidermal thickening that the
Clinical effects of compounds used to treat wrinkles
% of amelioration of
the parameter with the
most improvement
compared to target
parameter at baseline
Sum-up of study results
Compound, formulation
Duration of Type of
trial
study (cl,
db-bld
etc)
52%
51,6% (facial wrinkle counts)
(p<0.05 comp. to baseline)
niacinamide 4%
12 wks
51%
51% (mean improv. average
roughness of skin surface by laser
profilometry) (p<0.001 comp. to
50%
50%
12 wks
tretinoin 0.05%
24 wks
at least 50% improvement comp. to
baseline in 55% of the treated patients
(global response to treatment)
tretinoin 0.05%
24 wks
at least 50% improvement comp. to
baseline in 67% of the treated patients
(global response to treatment)
45%
% increase in
epidermal
thickness
Mean % of epidermal thickness
compared to target parameter at
baseline
75%
75% (epidermal thickness) 125% (rise n 17-βof dermal papillae) and 77% (n blood
estradiol
vesels) (p<0.01comp. to baseline and
0.01%
p<0.05 comp. to control)
Compound, Duratio Type of study Number
formulation n of trial (cl, db-bld
of
etc)
patients
24 wks
44.5%
tretinoin
44,5% (mean increase epidermal
thickness) (p<0.001 comp. to baseline but 0.05%
p>0.05 compared to vehicle)
Sex, Age
Skin
area
tested
rd, db - bld,
comp
18/36
post-m
wm, btw
45–55
facial skin daily at
night
Freq. of
appl.
Moraes,
2009
Ref.
58/359
41%
24 wks
multic, rd, dbbld, vc and
comp
mn and
wm, >=18
yrs
facial skin daily at
night
Kang, 2001
38%
estradiol
0.01% and
glycolic
acid 15%
24 wks
rd, db-bld, split 22/65
face vc
post-m
wm, btw
39- 83
facial skin twice a
day
Fuchs, 2003
29.5%
tazarotene
29,5% (mean increase epidermal
thickness) (p<0.05 comp. to baseline but 0.1%
p>0.05 compared to vehicle)
24 wks
multic, rd, dbbld, vc and
comp
mn and
wm, >=18
yrs
facial skin daily at
night
Kang, 2001
27%
27% (increase in epidermal
thickness, p=0.0046 compared to
control)
glycolic
acid 15%
24 wks
rd, db-bld, split 21/65
face vc
post-m
wm, btw
39- 83
facial skin twice a
day
Fuchs, 2003
24%
24% (increase in epidermal
thickness, p<0.01 comp. to control)
tretinoin
0.05%
24 wks
mc, rd, dbl-bld, 62/125
vc
mn and
face,
daily
wm, 30- 65 neck, left
yrs
forearm
and hand
skin
Lowe, 1994
23%
23% (increase in epidermal
thickness, p=0.0045 compared to
control)
estradiol
0.01%
24 wks
rd, db-bld, split 22/65
face vc
post-m
wm, btw
39- 83
facial skin twice a
day
Fuchs, 2003
20.8%
20.8% (epidermal thickness) and 36%
(n blood vesels) (p<0.05 comp. to
baseline)
genistein
4%
24 wks
cl, rd, db bld, comp
post-m
wm, btw
45–55
facial skin daily at
night
Moraes,
2009
16.5%
16.5% (epidermal thickness) (p<0.05
comp. to control)
glycolic
acid 20%
12 wks
rd, db-bld, split 15
forearm vc
wm, 51- 68 forearm
yrs
skin
12%
12% (epidermal thickness) (no SS
measured)
lactic acid
12%
16 wks
open label
14
mn and
facial skin twice a
wm, 35- 50
day
yrs
Smith, 1996
9.1%
9,1% (epidermal thickness) (no SS
measured)
lactic acid
5%
16 wks
open label
10
mn and
facial skin twice a
wm, 35- 50
day
yrs
Smith, 1996
59/359
18/36
twice a
day
Chiu,
2007
wm, 40-75 yrs
periorbital
skin
twice a
day
Beitner
, 2003
wm, 40- 55 yrs
facial skin
daily
Barel,
1995;
Samuel
, 2005
daily at
Kang,
night
2001
tazarotene 0.1%
24 wks
multic, rd,
16 wks
and comp
open label
41% (facial wrinkle cts), 6,8%
(facial spot cts), 15.9% (facial pore
cts),
16,3% (facial evenness cts),
16.7% (facial corneal moisture) and
10% (facial skin erythema) (p<0.05
niacinamide 4%+ kinetin
0,03%
12 wks
rd, db-bld, 27
vc, split
face comp.
vitamin C 5% (Active C ®)
24 wks
59/359 mn and wm, >=18 facial skin
daily at
Kang,
yrs
night
2001
mn and wm, 35- facial skin
50 yrs
asian mn and wm, facial skin
30- 60 yrs
twice a
day
twice a
day
Smith,
1996
Chiu,
2007
rd, db-bld, 19
vc, split
low
neck/forear
m comp.
wm, 51- 59 yrs
low neck
and dorsal
aspects of
forearms
daily
Humbe
rt, 2003
wm, 31-49 yrs
facial skin
twice a
day
Kawad
a, 2008
db-bld, vc
14
)
34%
34% (mean improv. wrinkle grade
score, p<0.001 comp. to control and
baseline) 11,3% (mean improv. in Ra:
average roughness of skin surface,
p<0.05 comp. to control and p<0.01
comp. to baseline)
niacinamide 4%
8 wks
rd, db-bld,
split face
vc
33% (overall global assessment
grade) 29% (fine lines/wrinkles grade)
26% (skin roughness/dryness grade)
37% (skin hydration grade) (no SS
measured)
idebenone 1.0%
6 wks
rd, db- bld, 20/41
comp.
wm, 30- 65 yrs
facial skin
twice a
day
McDani
el,
2005
33% (periocular wrinkle score) 25%
(perioral wrinkle score) (no SS
measured)
mixture of human growth
24 wks
factors and cytokines (PSP ® Processed skin cell proteins-)
idebenone 0.5%
6 wks
open label
wm, 35- 65 yrs
facial skin
twice a
day
Hussai
n, 2008
rd, db- bld, 21/41
comp.
wm, 30- 65 yrs
facial skin
twice a
day
McDani
el,
2005
argireline 10% O/W emulsion 30 days
split
periorbital,
vc
rd, db-bld,
vc
10
wm
periorbital
skin
twice a
day
x/20
post-m wm, 4560 yrs
facial, neck twice a
and forearm day
skin
BlanesMira,
2002
Haftek,
2008
18/35
peri or post-m
facial and
wm, 45- 60 yrs
neck skin
li
30%
30%
)
30% (overall global assessment
grade) 27% (fine lines/wrinkles grade)
23% (skin roughness/dryness grade)
37% (skin hydration grade) (no SS
measured)
up to 30% (depth of
periorbital wrinkles measured
by skin topography, no SS
measured)
29
11
29,5% (mean improv. global clinical
score: hydratation, roughness,
suppleness, fine and coarse wkls,
radiance, lustreless, brown spots and
skin homogeneity) (p<0.001 comp. to
baseline)
vitamin C 5% and
madecassoside 0.1%
(Redermic ®)
24 wks
29.1% (wkl count) 9.72% (wkl
depth score) (p>0.05 compared to
control)
progesterone 2%
16 wks
rd, db-bld,
29% (clinical score of overall
severity, p<0.001 comp. to control)
23% (subject assessed overall skin
appearance) 30% (subject assessed
wkls, p<0.01 comp. to control)
tretinoin 0.05%
24 wks
mc, rd, db- 62/125 mn and wm, 30bld, vc
65 yrs
27% (periocular wrinkle depth
measured by microtopography, no SS
measured)
CoQ10 0.3%
24 wks
25% (clinical score fine lines,
p<0.05 comp. to baseline) 11%
(clinical score wkls, p<0.05 comp. to
baseline and control). By skin replica:
21.3% (mean total surface with wkls)
17.5% (Rz)
14,5% (Ra) 14%(mean length of
the surface with wkls) (p<0.05
retinol 1%+ lactose 5%+
glycolic acid 4%
12 wks
split
periorbital,
vc
rd, db-bld,
split face
vc
25,5% (average roughness -mayor
line-, p<0.05 comp. to baseline)
11,7% (average roughness -fine line
and texture-, p<0.05 comp. to
baseline) 20% (Shadow EW -fine line
and texture-, p<0.05 comp. to
baseline) (p>0.05 comp. to control)
>110 growth factors and
cytokines topical gel
(NouriCel-MD ®)
24 wks
rd, db-bld,
vc
23% (red. skin surface volume)
52% (roughness) 76% (scaling)
(measured by Visioscan) (p<0.05
compared to control)
ectoin 2%
4 wks
21% (mean reduction RZ-D:
average of the maximal depths of
roughness) (p=0.0005 compared to
estriol 0.3%
24 wks
rd, db-bld, 24
split
forearm vc
rd,
30/58
comparativ
e
20% (periocular score for sup. lines
and wkl, no SS calculated)
lactic acid 5%
16 wks
18,6% (periorbital wkl score,
p=0.0005 comp. to ctr) 15% (perioral
wkl score, p=0.01 comp. to ctr) 13%
(cheeks wkl score, p=0.006 comp. to
ctr) 8% (forehead wkl score, p=0.07
comp. to ctr)
ascorbic acid 10% and
12 wks
tetrahexyldecyl ascorbate 7%
rd, db-bld, 10
split face,
vc
18%
18.3% (decrease total length fine
line/wkl by quantitative image analisis,
p<0.10 compared to placebo)
pal-KTTKS
12 wks
18%
18% (mean reduction RZ-D:
average of the maximal depths of
roughness, p=0.002 compared to
estradiol 0.01%
24 wks
rd, dbl-bld, 93
split face
vc
rd,
28/58
comparativ
e
18% (overall assessment score,
p<0.05) 22% (fine wkls score, p>0.05)
22% (mottled hyperpigmentation
score, p>0.05) 42% (roughness score,
p>0.05) (p value compared to control)
lactic acid 8%
22 wks
rd, db-bld,
vc
17% (overall assessment score,
p<0.05) 22% (fine wkls score, p>0.05)
14% (mottled hyperpigmentation
score, p>0.05) 44% (roughness score,
p>0.05) (p value compared to control)
glycolic acid 8%
22 wks
17%
17% (periocular wkls score) 13%
(perioral wkls score) (p<0.05
compared to baseline)
17%
17% (Shadows N-S) 0.06% (Ra N-S)
(measured by skin surface image)
(p=0.03 compared to control)
13%
13% (fine wrinkles score) 12%
(global clinical score) (p<0.001
compared to baseline)
29%
29%
29%
27%
25%
Methods:
We performed a literature search in Pubmed among clinical trials with the
keywords “skin” and “wrinkle” or “aging” or “antiaging”. The search was done
within articles published in between 01.01.1999 and 01.06.2009; older articles
were included if they were mentioned as precedent in newer articles and the
methodology and results of the study were found to be appropriate and
reliable. The search yielded 476 articles. We manually looked for clinical trials
within the resulting list. The shaded lines in the tables indicate that no
statistical relevance was reached or no relevant statistics were published.
asian mn and wm, facial skin
30- 60 yrs
34% (global clinical score:
hydration, roughness, laxity,
suppleness, fine wrinkles and coarse
wrinkles. P<0.05 comp. to control)
14,5% (Ra, average roughness by
skin replica) and 13,2% (peak to
valley mean of roughness by skin
33%
Bernstein,
2001
Ref.
34%
33%
twice a
day
Freq. of
appl.
yrs
lactic acid 12%
li
Skin area
58/359 mn and wm, >=18 facial skin
45% (periocular score for sup. lines
and wkl) (no SS measured)
t b
38% (epidermal thickness,
p=0.00018 comp. to control)
multic, rd,
db-bld, vc
(p<0.05 comp. to control)
Epidermal thickness increase by compounds used to treat wrinkles
rd, db-bld, 25
vc, split
face comp.
rd, db-bld, 32
split face
vc
rd, db-bld, 17
split face
vc
Sex and age
and comp
(p<0.05 comp. to control)
50%
different agents were able to elicit.
lipoic acid 5%
50% (fine wkls score) 32% (overall
severity of photoageing score) 21%
(coarse wkls score) (p<0.05 comp. to
control)
control)
Numb
er of
patien
ts
dt
25%
b
li
d
t l)
vc
daily
Holzer,
2005
face, neck, daily
left forearm
and hand
skin
elderly volunteers periorbital
daily
skin
Lowe,
1994
40
wm, 35- 50 yrs
facial skin
twice a
day
Bertin,
2008
30/60
mn and wm, 2565 yrs
facial skin
twice a
day
Mehta,
2008
20
Hoppe,
1999
wm, 30- 60 yrs
forearm
twice a
day
Heinric
h, 2007
peri or post-m
wm, 41- 67 yrs
(mean age 53)
facial and
neck skin
daily
Schmid
t, 1996
mn and wm, 3550 yrs
-
facial skin
twice a
day
daily
Smith,
1996
Fitzpatr
ick,
2002
wm, 35- 55 yrs
facial skin
twice a
day
peri or post-m
wm, 43- 66 yrs
(mean age 54)
facial and
neck skin
daily
Robins
on,
2005
Schmid
t, 1996
24/74
wm, 40 -70 yrs
facial and
twice a
forearm skin day
Stiller,
1996
rd, db-bld,
vc
21/74
wm, 40 -70 yrs
facial and
twice a
forearm skin day
Stiller,
1996
mixture of human growth
8 wks
factors and cytokines
(Processed Skin Cell Proteins;
PSP®)
vitamin C (Cellex-C high12 wks
potency serum; Cellex-C
International, Toronto,
Ontario)
kinetin (Kinerase ®)
24 wks
open label
18
wm, 38- 65 yrs
facial skin
twice a
day
Gold,
2007
rd, db-bld,
split face
vc
19
mn and wm, 3672 yrs
facial skin
daily
Traikov
ich,
1999
open label
30
mn and wm, 3272 yrs
facial skin
twice a
day
7%
7% (clinician rated overall
appearance, p<0.05 compared to
control)
DMAE gel 3%
16 wks
mc, rd, db- 105/15 mn and wm, 35bld, vc
6
60 yrs
facial skin
-
5%
5% (wrinkle length by computer
image analysis, p=0.0005 compared
to control)
niacinamide
12 wks
rd, db-bld, 50
split face,
vc
wm, 35- 60 yrs
facial skin
twice a
day
McCull
ough J,
2002
Gross
man,
2005
Bissett,
2005
placebo controlled double blind studies, accepted measuring standards
4%
4.3% (mean reduction wkl volume
by PRIMOS system, p<0.05 compared
to control)
arctium lappa fruit extract
1,2%
4 wks
rd, split
face vc
wm, 39- 65 yrs
periorbital
skin
twice a
day
Knott,
2008
and defined objective endpoints are needed for the future.
0%
no significant clinical improvement
green tea cream 10% and
green tea supplementation
300 mg oral
8 wks
rd, dbl-bld, 13/30
vc
wm
facial and
arms skin
twice a
day
Chiu,
2005
Conclusion:
Tretinoin reduced facial wrinkles (-29 to -50%) and induced epidermal
thickening (+24 to +44.5%). Niacinamide (-34 to -52%) and lipoic acid (-51%)
showed similar efficacy on facial wrinkles, while estrogens were less effective
(-21% on facial wrinkles) but induced epidermal thickening (+75%).
The phytoestrogen genistein induced weaker epidermal thickening
(+20%) without showing convincing effects on wrinkles. Vitamin C had an
intermediate effect on wrinkles (-34% to -29%).
The collagen-inducing tripeptide pal-KTTKS (-18% wrinkles, no significant
difference to placebo), ectoin (-23%) and kinetin (-13%), and green tea
extracts had no effect at all.
Taken together, a simple global analysis of efficacy shows differences
between the agents already today, although higher quality randomized
23%
21%
estradiol by Wilcoxon test)
20%
18%
estriol by Wilcoxon test)
18%
17%
5%
open label
10
38
facial skin
Arianna Mastrofrancesco