Post‐inflammatory hyperpigmentation (PIH) is a common dermatologic complaint that affects different parts of the body. An international survey showed it affects almost 15% of the population; it is more prevalent in women [1, 2]. It has prominent effects on patients' quality of life, social, and psychological status [1, 3]. Different factors such as genetics, specific drugs, inflammation, and trauma such as sun exposure or acne play a role in the hyperpigmentation process. It usually appears as hyperpigmented macules or plaques, which can affect the dermis, epidermis, or both [2, 4]. While PIH is a common cause of axillary pigmentation, it is important to consider and rule out other potential etiologies such as erythrasma, freckling, and genetically associated pigmentation disorders like neurofibromatosis type 1 and acanthosis nigricans. These conditions should receive proper treatment instead of lightening agents [5, 6].

PIH pathogenesis is not fully explained yet, but there are several factors that affect it. Higher melanogenesis or melanin deposition in response to an inflammatory process or an external injury such as UV or shaving results in PIH. Damage in the basal layer of the epidermis, besides inflammatory markers like interleukin‐1, tumor necrosis factor (TNF), and epidermal growth factor (EGF) increases transport synthesis of melanin to the keratinocytes [7].

There is no standard treatment for PIH conditions. Studies suggest that prevention by sunscreen and other methods is useful since the duration of treatment can vary up to 8 years [8]. To date, there are several treatments for PIH, including topical steroids, niacinamide, retinoids, and laser or energy‐based device interventions [9, 10]. These methods can also have adverse effects such as irritation or erythema in the affected area.

Axillary has a different tissue in comparison to other parts of the body. It has more sebaceous and sweat glands, more hair follicles, and a higher water loss value through the epidermis. This structure makes a weaker skin barrier in that part [11]. Axillary hyperpigmentation (AH) is a dermatologic complaint, especially in women with darker skin. Hyperpigmentation in the axillary is more common than in other parts of the skin because of irritation and inflammation usually caused by body folds, friction, hair plucking, shaving, deodorants, and using whitening agents [11, 12, 13]. Although there are different treatment options for skin pigmentation, there is no standard treatment for AH.

In this study, we aim to address the efficacy and safety of the studied treatment modalities for AH. This review study provides readers an overview of current treatment options for AH and helps them to make better treatment and research plans on this topic.

The aim of this systematic study is to investigate the efficacy and safety of the studied treatment modalities for AH. It follows the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) [14].

Ten articles were enrolled (Table 1). The retrieved articles are categorized into three groups: “topical treatments,” “light‐ and laser‐based modalities,” and “comparing topical and light‐ and laser‐based modalities.”

In this study, we found that both topical in addition to light and laser‐based therapies are effective. The studied topical agents for AH were niacinamide, desonide, CREO, AHA, HQ, Citrus Sinensis L., and PFLE. Light and laser therapies applied for AH were QS‐Nd YAG and IPL. Many of these treatments are being used off‐label for AH.

AH is a very common aesthetic complaint, especially in dark‐skinned women. Skin barriers are weaker in the axillary area because of higher water loss through the epidermis and the presence of more sebaceous and sweat glands. Also, using chemical deodorants, shaving, and friction cause irritation and skin tissue damage, which result in PIH [11, 22, 25]. In a study evaluating the histopathology of hyperpigmented axillae in Filipino patients, they hypothesized that darkening of the axillary is mild PIH. It is characterized by skin irritation or stimulation (mostly by hair plucking), which results in a melanin increase in the epidermis [13].

However, there exist no gold standard treatments for it. According to literature, it has been proposed that AH is a type of PIH. There exist various treatment strategies for PIH, including topical therapy, including hydroquinone, which is commonly combined with topical retinoid and steroid, as in Kligman formula, chemical peels such as Glycolic and salicylic acid, and laser therapies including Q‐switched ruby, picosecond, and Q‐switched Nd:YAG lasers [26]. Applying lasers in dermatologic diseases has a wide spectrum. Among these, we can mention hair removal, scar treatment, rejuvenation, post‐acne erythema, tattoo removal, and skin pigmentation conditions [27, 28, 29, 30].

Pablo et al. compared the effectiveness and safety of niacinamide, desonide, and placebo in treating AH in an RCT with 24 females. Niacinamide has anti‐inflammatory effects that cause depigmentation by prohibiting the melanosomes from going from the melanocyte to the keratinocyte [31]. Desonide is a synthetic, low‐potency corticosteroid and is generally considered safe. Topical corticosteroids can also reduce the PIH and cause depigmentation. The results of that study showed that both agents were effective; however, desonide had a superior blanching impact. They also proposed that desonide might decrease the inflammation involving the basal membrane disruption or stop the pathways which postpone the recovery. No change in the melanocyte count was noted, and they concluded that melanogenesis relies on enhanced melanin production and not on the cell number alterations [32].

In another study with 153 participants, the efficacy of CREO, HQ, and placebo was compared. The oil of the grass Cyperus rotundus (purple nutsedge) has anti‐inflammatory in addition to antipigmenting effects (as effective as HQ) and it inhibits tyrosinase activity. The authors of that study concluded that CREO had significantly better anti‐inflammatory and depigmenting effects and a decrease in hair growth compared to HQ. Cyperus rotundus has anti‐inflammatory and antioxidant effects because of its polyphenol, tannin, and flavonoid components [33, 34]. It also showed inhibitory effects on melanogenesis in B16F10 melanoma cells [35].

Another study examined the efficacy of PFLE serum ( Perilla frutescens L. leaves extract) on α‐melanocyte‐stimulation hormone (α‐MSH), which is a chemical involved in melanogenesis. This herbal medicine product contains a variety of potent antioxidants in leaves, having various biological effects. The results showed that this serum is effective in axillary whitening and causes a significant reduction in melanin and the erythema index in comparison to baseline and improves the skin tone [17].

Two other reports showed the efficacy of glycolic acid and sweet orange peel. Glycolic acid with modified pH showed to have anti‐inflammatory and epidermal renewal and collagen production stimulative effects [36]. Sweet orange peel has flavonoid components, which affect melanin production through their tyrosinase enzyme inhibitory nature. These components can inhibit melanogenesis [37, 38]. Also, hesperidin, another component in citrus peels, showed inhibition of melanin synthesis in melanoma B16 cells [39].

Two observational studies exclusively investigated the use of Q‐switched Nd:YAG on AH, and another study compared Q‐switched Nd:YAG with IPL. The first observational study on nine patients [12] evaluating the use of nanosecond 1064 nm Q‐switched Nd:YAG showed that 33.3% of individuals had excellent results, and 55.5% manifested significant enhancement in AH. In this regard, Ghannam et al.'s observational study on 17 females showed that low‐fluence Q‐switched 1064‐nm Nd:YAG laser is a good treatment option for AH [21]. They proposed that it leads to good‐to‐excellent enhancement after a minimum of 3 sessions. Additionally, it was concluded that the outcome was not related to increased session numbers. It has been shown that QS laser can decrease melanin granules and melanosomes and is effective for treating various pigmentation diseases, namely melasma, as revealed by histologic studies [40].

Regarding comparison of Q‐switched Nd:YAG and IPL for AH, an study on 22 participants was conducted by Amornpektul et al. [22]. The result of that study suggested that both modalities are useful with no significant difference in the result. IPL showed a lower level of pain during the procedure compare to Q‐switched Nd:YAG. A serious adverse effect of IPL, especially in patients with darker skin, is hyperpigmentation; however, it is rare [22]. Previous studies showed efficacy and safety of IPL in treatment of hyperpigmentations in other parts of the body [41, 42, 43]. Due to being cost–benefit and commonly used in dermatology, IPL seems to be a very good choice for AH.

One study [23] evaluated the efficacy of IPL and AHA on 20 subjects. AHA is a chemical peeling agent belonging to a group of organic acids. Furthermore, it has been suggested that AHA can inhibit the tyrosinase enzyme. The results of that study showed that both of these modalities are effective in lightening axillae and rejuvenating underarm skin and enhancing smoothness. However, IPL was more effective than AHA regarding whiteness (85%) and smoothness (30%), respectively. Moreover, adverse effects of AHA were more serious than those of IPL due to the high concentration (40%) of AHA and low pH of 2.

Although our study is a comprehensive review of available treatments for AH, it also has limitations. The available studies on this topic are limited, mostly with small sample sizes and short follow‐up periods. There is also a lot of variation in treatment methods, which made us unable to do a meta‐analysis. These limitations are due to the lack of standard treatment for AH and the few published studies on this topic.

In conclusion, all topical, light, and laser‐based devices are useful treatments for AH. The most frequently used laser in treating AH was QS Nd‐YAG without having any severe adverse effects. Various topical treatments, including niacinamide, desonide, HQ, AHA, and a few herbal extracts, were shown to be effective for AH. However, based on this review, very few studies are available in the literature, and larger randomized studies in this field are essentially needed. This study shed light on current available treatments, as well as giving ideas to readers to conduct new studies in the future to improve treatment outcomes and potential innovations.

Conceptualization: I.E., Y.K., S.M.V.; data curation: S.S., E.P., S.H.; methodology: S.S., E.P.; supervision: I.E., S.M.V.; validation: S.H., Y.K.; writing – original draft preparation: S.M.V., S.S., Y.K., E.P.; writing – review and editing: S.M.V., I.E., S.H. All authors have read and agreed to the published version of the manuscript.

The authors declare no conflicts of interest.