Cosmetic Color Improvement of the Nipple-Areola
Complex by Optimal Use of Tretinoin and Hydroquinone
Kotaro Yoshimura, MD,* Akira Momosawa, MD,* Asami Watanabe, MD, †Katsujiro Sato, MD,* Daisuke Matsumoto, MD,* Emiko Aiba, MD,* Kiyonori Harii, MD,*
Takahiro Yamamoto, MD, ‡ Takao Aoyama, PhD, § and Tatsuji Iga, PhD §*Department of Plastic and Reconstructive Surgery and §Pharmacy, University of Tokyo, Graduate School of Medicine,†Ritz Medical Clinic, Tokyo, ‡ Oita Dermatologic Clinic, Oita City, Japanbackground. A successful treatment to improve the color ofnipple-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 the NAC.
methods. The protocol was composed of two phases: bleaching phase (4–8 weeks) and healing phase (4–6 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 to the 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 hydro-

quinone alone was continually applied in the healing phase until the reactive erythema was eliminated. Fifteen female patientswere 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 physician’s estimation, and 11 patients (73%) satisfied with
their final results. The treatment was repeated after a 1-monthinterval 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. This approach appeared to be most effective forcosmetic improvement of NAC color among treatments available so far.

K. YOSHIMURA, MD, A. MOMOSAWA, MD, A. WATANABE, MD, K. SATO, MD, D. MATSUMOTO, MD, E. AIBA, MD, K.
HARII, MD, T. YAMAMOTO, MD, T. AOYAMA, PHD, AND T. IGA, MD HAVE INDICATED NO SIGNIFICANT
INTEREST WITH COMMERCIAL SUPPORTERS.

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 thelatter 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 darklooking NAC from childhood, but others develop
them in adolescence or later. Up-regulations of female
hormones after adolescence could affect the color of
the NAC, and repeated mechanical stimulation suchas rubbing by undergarments or sexual habits cancause postinflammatory hyperpigmentation of theNAC. Additionally, women of some races with darkskin often have dark NACs.

Address correspondence and reprint requests to: Kotaro Yoshimura,MD, Department of Plastic and Reconstructive Surgery, Graduate
School of Medicine, University of Tokyo, or e-mail: yoshimura-pla@
h.u-tokyo.ac.jp.

No satisfactory method has ever been reported fortreatment 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-hydroxyacids 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 impossible.
The authors previously described an aggressive andoptimal use of tretinoin along with hydroquinone forvarious kinds of skin hyperpigmentation.1,2 More than
8,000 patients with hyperpigmented skin lesions havebeen 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.

© 2002 by the American Society for Dermatologic Surgery, Inc. • Published by Blackwell Publishing, Inc.
ISSN: 1076-0512/02/$15.00/0 • Dermatol Surg 2002;28:1153–1158

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yoshimura et al.: improvement of nipple-areola complex

To our knowledge, this paper is the first one to demonstrate successful results on NAC color modification.

Dermatol Surg

28:12:December 2002

Preparation of Ointments

the pigmentation is aggressively treated, and transient adverse skin effects such as erythema and irritation are usuallyobserved. Once satisfactory improvement is obtained, thehealing phase is started in order to reduce the erythema andinflammation, taking care not to induce new postinflammatory hyperpigmentation.

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 (KAointment) 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 HQAA 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 (4C) place.

Bleaching phase. Tretinoin gel and HQ-LA ointment wereapplied to the NAC twice a day. 0.2% tretinoin was used
initially. Tretinoin gel was applied only on NAC areas usinga small cotton-tip applicator, while HQ-LA ointment wasapplied beyond the NAC area (e.g., all over the whole breast
mound). In cases in which severe irritant dermatitis was induced by HQ-LA ointment, HQ-AA or KA ointment wasused instead. Patients were requested to visit our hospital at
1, 2, 4, 6 and 8 weeks after starting this treatment, and every 4 weeks afterward. 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 4–8 weeks to finish this phase. If thepatients desire further improvement, a second treatment
course with the same protocol can be started after 4–6
week’s interval ( healing phase described below).

Evaluations of Results

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 inwhich 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 in either
the bleaching or healing phase.

Patients and Methods

Clinical evaluations (objective). Photographs were taken forevery 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” (improvement is apparent and the result isimpressive), “good” (improvement can be recognized easily),“fair” (improvement can be recognized), and “poor” (improvement cannot be recognized via photos).
Patient satisfaction (subjective). Patients were interviewed
about their level of satisfaction with the clinical results after
the treatment. The patient was requested to estimate theclinical result and select one of three categories: “very satisfied,” “slightly satisfied,” and “not satisfied.”

Patients
Each ointment was topically applied under signed informed
consent in 19 Japanese women with complaints about their
NAC color, and 15 of them who were followed up for morethan 12 weeks were analyzed in this study. The other 4 patients could not be followed up for more than the 12 weeks
minimum required, and some of them might have discontinued treatment because of irritation, although their reasonsremain unclear. The age of patients varied from 18 to 42year-old (age  32.1  4.2; mean  SD).

Treatment Protocol
Our bleaching protocol is composed of two phases: ableaching phase and a healing phase. In the bleaching phase,

Results
In general, erythema was seen in a few days, followedby continual scaling during the first week. Erythemaand scaling were usually seen continually 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 mostcases. During the healing phase, erythema was gradually reduced, while the improvement in NAC color
was maintained.
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 hyperpigmentationon the surrounding mound induced by the first course.

Dermatol Surgyoshimura et al.: improvement of nipple-areola complex

28:12:December 2002

1155

Of 15 patients, HQ-AA ointment was used as an alternative to reduce irritant dermatitis in 2 cases during
the bleaching phase and 4 cases during the healing
phase, while KA ointment was used in one case during
the healing phase. No allergic contact dermatitis tohydroquinone was seen in this study.
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 theother 3 cases. Some improvement was seen in 12 of 15
patients (80.0%).
Six patients achieved sufficient satisfaction with theresults, 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 Figures 1–4.

Discussion
It is generally quite difficult to treat disfiguring colorof the NAC, so no satisfactory treatment has been reported so far. Laser treatments such as Q-switch rubylaser frequently result in depigmentation and/or scarring (Figure 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, althoughpatients experience unpleasant irritant 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 forwhich is mentioned below.
Since Kligman and Willis3 introduced their depigmenting formula, a number of products based on it,such as Tri-Luma (Galderma Laboratories, Cedex, France),
have become commercially available. These products
contain tretinoin and hydroquinone along with corti-

Table 1. Summarized Data of Clinical Results
Patient satisfaction

Excellent
Good
Fair
Poor
Total

Very satisfied

Slightly satisfied

Not satisfied

Total

2
4
0
0
6

0
3
1
1
5

0
0
2
2
4

2
7
3
3
15

Figure 1. Case 1. A 25-year-old woman who complained about thecolor 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 byapplication 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.

costeroid, and can let patients treat their pigmentation
simply and without having severe irritation. However,
we believe that corticosteroids reduce not only irritantdermatitis but also depigmenting effects of tretinoin
by suppressing keratinocytes proliferation and epidermal turnover. Indeed, based on our initial experiences,simultaneous use of corticosteroids and tretinoin reduced significantly the effectiveness of this treatment.
In addition, the separate preparation of tretinoin andhydroquinone is important, because it enables differential use of the two agents with regards to application areas and periods, which is essential in our protocol. 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

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yoshimura et al.: improvement of nipple-areola complex

Figure 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.

area, including the surrounding area, and 4 to use hydroquinone for at least 4 more weeks after cessationof tretinoin application. The 3rd and 4th points arequite important to avoid postinflammatory hyperpigmentation. Strictly speaking, the optimal amount oftretinoin to administer changes day by day with skinconditions: condition of the stratum corneum, thestate of tolerance to tretinoin, and personal variances.
The biological roles of tretinoin and hydroquinone
in this treatment should be clearly understood. The
authors think that the role of tretinoin in this protocol
is to discharge the melanin granules out of the epidermis.4 Tretinoin can directly accelerate epidermal turnover (promote differentiation of keratinocytes) andindirectly 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

Dermatol Surg

28:12:December 2002

Figure 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 hyperpigmentation.

by inducing heparin-binding EGF like growth factor(HB-EGF) secretion from suprabasal keratinocytes.5–7
These beneficial effects induced by tretinoin are specific for retinoids—they cannot be obtained by chemical peeling agents such as AHA and TCA—and can begreatly suppressed by corticosteroids. The antiretinoid
effects of corticosteroids seen in vivo are partly explained by the down-regulation of keratinocyte growth
factor expression from dermal fibroblasts induced bycorticosteroids.8
The role of hydroquinone, on the other hand, is tostrongly suppress production of new melanin. This isquite important in the present treatment because tretinoin appears not to suppress new melanogenesis asshown in our previous study using pigmented skinequivalents.4 According to our experiences, the effectiveness of hydroquinone is far larger than that ofDermatol Surg

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yoshimura et al.: improvement of nipple-areola complex

1157

Figure 5. Nipple and areola treated with laser therapy (the type oflaser is unknown) sometimes demonstrate white scarring. It is almost impossible to repair the disfiguring appearance.

sired. Postinflammatory hyperpigmentation could betreated in most cases with HQ-AA ointment in a few
months. Tretinoin and hydroquinone, used mildly andcarefully, can treat it more quickly.

Conclusions
Figure 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).

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.

References
kojic acid, which can not necessarily prevent postinflammatory hyperpigmentation induced during thebleaching phase. It is our understanding that application of corticosteroids is not beneficial to avoid postinflammatory hyperpigmentation.
Virtually the only possible complication seen in thisstudy was postinflammatory hyperpigmentation because of irritant dermatitis induced by aggressive useof 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. It cannot be denied that pigment darkening
could recur after treatment. Daily rubbing of the tissue
by undergarments could induce repeated inflammation,
followed by postinflammatory hyperpigmentation.
Continual application of hydroquinone can prevent thisin most cases, or the treatment can be repeated, if de-

1. Yoshimura K, Harii K, Shibuya F, Aoyama T, Iga T. A new
bleaching protocol for hyperpigmented skin lesions with a highconcentration 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. Kligman AM, Willis I. A new formula for depigmenting humanskin. Arch Dermatol 1975;111:40–8.
4. Yoshimura K, Tsukamoto K, Okazaki M, et al. Effects of all-transretinoic acid on melanogenesis in pigmented skin equivalents andmonolayer culture of melanocytes. J Dermatol Sci 27suppl1,
2001;27:68–75.
5. Yoshimura K, Uchida G, Okazaki M, Kitano Y, Harii K. Differential expression of heparin-binding EGF-like growth factor (HBEGF) mRNA in normal human keratinocytes induced by a varietyof natural and synthetic retinoids. Exp Dermatol, in press.
6. Stoll SW, Elder JT. Retinoid regulation of heparin-binding EGFlike growth factor gene expression in human keratinocytes andskin. Exp Dermatol 1998;7:391–7.
7. Xiao JH, Di Feng X, 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.
8. Chedid M, Hoyle JR, Csaky KG, Rubin JS. Glucocorticoids inhibit keratinocyte growth factor production in primary dermal fibroblasts. Endocrinology 1996;137:2232–7.

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CommentaryThis article provides an interesting treatment approach to anarea of cutaneous pigmentation sometimes not assessed by dermatologists worldwide. In women of Fitzpatrick skin type III or
higher, it is possible to develop increased pigmentation of thenipple-areola complex. Some of this pigmentation may be genetic, but the most common source of this darkening is postinflammatory hyperpigmentation due to the rubbing of undergarments intended to support the breasts. This irritation may be
due to the design of the brassiere, but also may be impacted by
the construction of the garment and the fabric selected. In thepast 2 years, a new area of dermatologic research has been
funded by Milliken Company, Spartanburg, SC. This company
has given their research and development division the challenge
of developing a fabric that decreases cutaneous rubbing friction
and prevents maceration as well as new undergarment manufacturing techniques to minimize the irritation caused by fabricseams. The outcome of this research effort has been the development of a new fabric garment line called DermaSense. I mention this as an aside, since many times dermatologists do notconsider the effects of clothing on dermatoses of the skin. This

article brings to light an important side-effect of clothing friction in a sensitive area of the female body, namely the nippleareola complex. The authors have applied an approach mostcommonly used to lighten the skin of the face to the nipple-areola complex. The combination of hydroquinone, a potent melanocyte toxin, with tretinoin gel, an inhibitor of melanin transfer, and lactic acid, a penetration enhancer, functions to ensure
an optimal decrease in nipple-areola complex melanization.
The authors astutely mention that the hydroquinone must becontinued for at least 4 weeks after discontinuation of the tretinoin. The biggest problem in the treatment of postinflammatory hyperpigmentation of this type is recurrence due to continuation of the inciting factor. Fortunately, intense dermatologic
research within the fabric industry is leading to new technologies that may be important in a variety of pigmentary and eczematous dermatoses in the near future.

Zoe Diana Draelos, MD
High Point, NC