Background: A successful treatment to improve the color
of nipple-areola complex (NAC) has never been reported,
although the number of women seeking the more attractively
colored NAC is not small.
Objective: To determine the effectiveness of our bleaching
protocol for cosmetic improvement of NAC.
Methods: The protocol was composed of two phases: bleaching
phase (4-8 weeks) and healing phase (2-6 weeks). 0.2-0.4%
tretinoin aqueous gel was applied concomitantly with 5%
hydroquinone, 7% lactic acid ointment for bleaching twice
a day. Tretinoin was applied on NAC with a small cotton
applicator, while hydroquinone was widely applied beyond
the NAC area. After obtaining sufficient improvement in
NAC color, the application of tretinoin was discontinued
and hydroquinone alone was continually applied in the healing
phase until the reactive erythema was eliminated. Fifteen
female patients were involved in this study.
Results: The average treatment period was 16.6 weeks. Improvement
of NAC color was obtained in 12 patients (80 %) by the
physicians' estimation, and 11 patients (73 %) satisfied
with their final results. The treatment was repeated after
a 1-month interval of tretinoin application in 4 patients:
2 desired further improvement in color, and 2 had the second
course conducted to treat the postinflammatory hyperpigmentation
on the surrounding mound induced by the first course.
Conclusion: The treatment appeared to be most effective
for cosmetic improvement of NAC color among treatments
available so far.
The number of females seeking a better-looking nipple-areola
complex (NAC) is not small. Some patients complain about
the size of nipple and/or areola, and others about the
color of NAC; the number of the latter is apparently greater
in Japan. In general, patients prefer lighter color to
darker color. An NAC which looks bright pink is thought
to be more attractive than a dark-brown one. Some patients
have dark-looking NAC from childhood, but others develop
them in adolescence or later. Hormones and/or repeated
inflammations are suspected to affect the color of the
NAC in the latter case.
No satisfactory method has ever been reported for treatment
of NAC color, although there are several options: laser
therapies, chemical peeling and tattooing. Lasers, such
as Q-switch ruby laser, Q-switch Nd:YAG laser, and dye
lasers, can change the color, but the results are often
disappointing and can be miserable. Laser treatments for
NACs sometimes lead to depigmentation and/or scarring,
and it is hard to get a homogenous and natural appearance.
Chemical peeling such as alpha-hydroxy acids or TCA combined
with a bleacher such as hydroquinone is minimally effective
in changing NAC color. Tattooing with white or pink color
leads to unnatural appearance, recovery from which is almost
The authors previously described an aggressive and optimal
use of tretinoin along with hydroquinone for various kinds
of skin hyperpigmentation (1, 2). More than 8,000 patients
with hyperpigmented skin lesions have been treated with
the original method or its modifications in our facility
over the past 7 years with successful overall results.
In the present study, the modified protocol was applied
to the patients who wanted improved NAC color, and the
results were satisfactory. To our knowledge, this paper
is the first one to demonstrate successful results on NAC
Patients and Methods
Preparation of Ointments: Tretinoin aqueous gels (tretinoin
gel) at 2 different concentrations (0.2, and 0.4 %) were
originally prepared at the Department of Pharmacy, University
of Tokyo, Graduate School of Medicine. The precise regimen
of tretinoin aqueous gel was described before (2). An ointment
including 5% hydroquinone and 7% lactic acid (HQ-LA ointment),
an ointment including 5% hydroquinone and 7% ascorbic acid
(HQ-AA ointment), and an ointment including 5% kojic acid
(KA ointment) were also prepared as well. Plastibase (petrolatum
polyethylene ointment base, Taisho Pharmacology, Osaka,
Japan) was used as the ointment base of the HQ-LA ointment,
while the hydrophilic ointment was used for the HQ-AA and
the KA ointments. Because tretinoin gel, HQ-LA, HQ-AA,
and KA ointment (especially tretinoin gel) are pharmacologically
unstable, fresh ointments were prepared at least once a
month and stored in a dark and cool (4oC) place.
Evaluations of results:
1) Clinical evaluations: Photographs were taken for every
patient at baseline and after the treatment, and two experienced
doctors (a dermatologist or cosmetic surgeon) who did not
perform this treatment evaluated the clinical results via
the photographs. The results were classified into 4 categories; "excellent" (considerably
improved), "good" (moderately improved), "fair" (slightly
improved), and "poor" (no change or worse).
2) Patient satisfaction: Patients were interviewed about
their level of satisfaction with the clinical results after
the treatment. The patient's feeling was categorized into; "very
satisfied", "slightly satisfied", and "not
Patients: Each ointment was topically applied under signed
informed consent in 19 Japanese women with complaint about
their NAC color, and 15 of them who were followed up for
more than 12 weeks were analyzed in this study. The age
of patients varied from 18 to 42 years old (age=32.1±4.2;
Treatment protocol: Our bleaching protocol is composed
of two phases, a bleaching phase and a healing phase. In
the bleaching phase, the pigmentation is aggressively treated,
and transient adverse skin effects such as erythema and
irritation are usually observed. Once satisfactory improvement
is obtained, the healing phase is started in order to reduce
the erythema and inflammation, taking care not to induce
new postinflammatory hyperpigmentation.
1) bleaching phase: Tretinoin gel and HQ-LA ointment were
applied to the NAC twice a day. 0.2% tretinoin was used
initially. Tretinoin gel was applied only on NAC areas
using a small cotton-tip applicator, while HQ-LA ointment
was applied beyond the NAC area (e.g. all over the whole
breast mound). In cases in which severe dermatitis was
induced by HQ-LA ointment, HQ-AA or KA ointment was used
instead. Patients were requested to visit our hospital
at 1, 2, 4, 6 and 8 weeks after starting this treatment,
and every 4 weeks afterwards. When the appropriate skin
reaction (that is, mild erythema and scaling) was not observed
at 1 week, the concentration of tretinoin was changed to
0.4%. In most cases, it took 4 to 8 weeks to finish this
phase. If the patients desire further improvement, the
second treatment course with the same protocol can be started
after 4-6 weeks' interval (= healing phase described below)
of tretinoin gel application.
2) healing phase: After sufficient improvement of NAC color
was obtained, the application of tretinoin gel was discontinued,
but that of HQ-LA ointment was continued. In cases in which
erythema was not reduced at all after a few weeks' application
of HQ-LA ointment, HQ-LA ointment was also discontinued
and HQ-AA or KA ointment was applied until the redness
was sufficiently reduced. It usually took 4-6 weeks to
complete this phase. The total period of a single treatment
course to finish both phases was usually 8-12 weeks. Topical
corticosteroids were not employed either in the bleaching
or healing phase.
In general, erythema was seen in a few days, followed by
continual scaling during the first week. Erythema and scaling
were usually continually seen throughout the bleaching
phase. Formation of scales (accumulated horny layers) and
itching were also seen in some cases during the second
week. After the scales repeatedly came off, improvement
of NAC color was usually obtained. Sufficient improvement
in NAC color was obtained after a bleaching phase of 4-8
weeks in most cases. During the healing phase, erythema
was gradually reduced, while the improvement in NAC color
The average treatment period of 15 patients was 16.6 weeks,
because some cases underwent the second course. The second
treatment course was performed in 4 cases: 2 desired further
improvement in color, and 2 were treated for postinflammatory
hyperpigmentation on the surrounding mound induced by the
The clinical results and the patients' satisfaction were
summarized in Table 1. Two patients were evaluated as "excellent",
7 cases as "good", and 3 cases as "fair".
No improvement was clinically observed in the other 3 cases.
Some improvement was seen in 12 of 15 patients (80.0%).
Six patients achieved sufficient satisfaction with the
results, and 5 had slight satisfaction. The other 4 cases
were not satisfied with their results. Some satisfaction
was recognized by 11 of 15 patients (73.3%).
The representative 4 cases are shown in Figs. 1-4.
It is generally quite difficult to treat disfiguring color
of the NAC, so no satisfactory treatment has been reported
so far. Laser treatments such as Q-switch ruby laser frequently
result in depigmentation and/or scarring (Fig. 5). Based
on our experiences with an aggressive bleaching treatment
using tretinoin and hydroquinone on thousands of patients,
the authors applied the modified protocol to treat NAC
color, and found it was sufficiently effective. This protocol
can eliminate melanin pigmentation quite effectively, although
patients experience unpleasant dermatitis, especially in
the first 2 weeks. Some of the adverse effects during the
bleaching phase can be somewhat suppressed by use of antioxidant
lotions, moisturizing lotions/creams, and/or oils. Corticosteroid
ointments should not be used in this treatment, the reason
for which is mentioned below.
We think the critical points of this protocol are: 1) to
use a high concentration of tretinoin "aqueous gel ",
which means an aggressive and optimal use of tretinoin,
2) to not use corticosteroid at all, 3) to use tretinoin
only on the hyperpigmented lesion with a small cotton-tip
applicator and use hydroquinone over the large area, including
the surrounding area, and 4) to use hydroquinone for at
least 4 more weeks after cessation of tretinoin application.
The 3rd and 4th points are quite important to avoid postinflammatory
hyperpigmentation. Strictly speaking, the optimal amount
of tretinoin to administer changes day by day with skin
conditions: condition of the stratum corneum, the state
of tolerance to tretinoin, and personal variances.
The authors think that the role of tretinoin in this protocol
is to wash the melanin granules out of the epidermis (3).
Tretinoin can directly accelerate epidermal turnover (promote
differentiation of keratinocytes) and indirectly promote
the proliferation of keratinocytes. The reason for epidermal
hyperplasia after tretinoin application had been unknown,
but tretinoin was recently found to promote proliferation
of keratinocytes by inducing heparin-binding EGF like growth
factor (HB-EGF) secretion from suprabasal keratinocytes
[5,6]. These beneficial effects induced by tretinoin are
greatly suppressed by corticosteroids, and that is the
reason why corticosteroids were not used in the present
protocol. The anti-retinoid effects of corticosteroids
seen in vivo are partly explained by the down-regulation
of keratinocyte growth factor expression from dermal fibroblasts
induced by corticosteroids . The reason why the pigmentation
in the upper dermis is also reduced by tretinoin application
remains to be elucidated.
The role of hydroquinone, on the other hand, is to strongly
suppress production of new melanin. This is quite important
in the present treatment because tretinoin appears not
to suppress the melanin production as shown in our previous
study using pigmented skin equivalents . According to
our experiences, the effectiveness of hydroquinone is far
larger than that of kojic acid, which can not necessarily
prevent postinflammatory hyperpigmentation induced during
the bleaching phase.
Virtually the only possible complication seen in this study
was postinflammatory hyperpigmentation because of dermatitis
induced by aggressive use of tretinoin and/or hydroquinone.
In our experience, it occurred on breasts more frequently
than on faces with the same treatment. Therefore, it may
be better to use tretinoin on the area 2-3 mm in from the
areola margin, and hydroquinone just on the exact area
of the areola. Postinflammatory hyperpigmentation could
be treated in most cases with HQ-AA ointment in a few months.
Otherwise, mild use of tretinoin with hydroquinone can
In the present clinical trials, our protocol improved NAC
color without leaving any scars or depigmentation.
This is the first report to demonstrate a successful
treatment for improvement of NAC color.
Table 1. Summarized
data of clinical results
very satisfied slight satisfied not satisfied total
excellent 2 0 0 2
good 4 3 0 7
fair 0 1 2 3
poor 0 1 2 3
total 6 5 4 15
1. Yoshimura K, Harii
K, Shibuya F, Aoyama T, Iga T. A new bleaching
protocol for hyperpigmented skin lesions with a
high concentration of all-trans retinoic acid aqueous
gel. Aesthetic Plast Surg 1999; 23: 285-91.
2. Yoshimura K, Harii K, Aoyama T, Iga T. Experience of
a strong bleaching treatment for skin hyperpigmentation
in Orientals. Plast Reconstr Surg, 2000; 105: 1097-108.
3. Yoshimura K, Tsukamoto K, Okazaki M, et al. Effects
of all-trans retinoic acid on melanogenesis in pigmented
skin equivalents and monolayer culture of melanocytes.
J Dermatol Sci 2001; 27suppl1: 68-75.
4. Yoshimura K, Uchida G, Okazaki M, Kitano Y, Harii K.
Differential expression of heparin-binding EGF-like growth
factor (HB-EGF) mRNA in normal human keratinocytes induced
by a variety of natural and synthetic retinoids. Exp Dermatol,
5. Stoll SW, Elder JT. Retinoid regulation of heparin-binding
EGF-like growth factor gene expression in human keratinocytes
and skin. Exp Dermatol 1998; 7: 391-7.
6. Xiao JH, Feng X, Di W, et al. Identification of heparin-binding
EGF-like growth factor as a target in intercellular regulation
of epidermal basal cell growth by suprabasal retinoic acid
receptors. EMBO J 1999; 18: 1539-48.
7. Chedid M, Hoyle JR, Csaky KG, Rubin JS. Glucocorticoids
inhibit keratinocyte growth factor production in primary
dermal fibroblasts. Endocrinology 1996; 137: 2232-7.
Fig.1. Case 1. A 25-year-old
woman who complained about the color of her NAC
and some pigmentation of the breast mound underwent
the treatment (A: before treatment); 0.2 % tretinoin
gel was used for 4 weeks together with HQ-LA ointment,
followed by application of HQ-LA ointment alone
for 4 weeks (B: after treatment of 8 weeks). NAC
color was improved though the pigmentation of the
breast mound was still observed.
Fig.2. Case 2. A 28-year-old woman underwent the treatment
(A: before treatment); 0.2 % tretinoin gel was used for
4 weeks together with HQ-LA ointment, followed by application
of HQ-LA ointment for 2 weeks and HQ-AA ointments for 4
weeks (B: after treatment of 10 weeks). NAC color was improved,
but postinflammatory hyperpigmentation was left on the
mound in this case.
Fig.3. Case 3. A 22-year-old
woman underwent the treatment (A: before treatment).
Because she underwent mastopexy operation before,
she had a linear scar on the areolar margin. 0.2
% tretinoin gel was used for 1 week and 0.4 % tretinoin
for 3 weeks, followed by application of HQ-LA ointment
for 6 weeks. (B: after treatment of 10 weeks).
NAC color was improved without leaving any postinflammatory
Fig.4. Case 4. A 34-year-old
woman underwent the treatment (A: before treatment).
Bleaching was performed with 0.2 % tretinoin gel
and HQ-LA ointment for 6 weeks, and erythema disappeared
after 6 weeks of healing phase (B: after treatment
of 12 weeks).
Fig. 5. Nipple and areola treated with laser therapy (the
type of laser is unknown) sometimes demonstrate white
scarring. It is almost impossible to repair the disfiguring