Melasma is considered as a common acquired facial hypermelanosis. It was derived from the Greek word (melas), which means black. It presents as symmetrically distributed hyperpigmented macules, which can be confluent or punctate, and occurs on sun-exposed areas. The predominant areas affected by melasma are cheeks, upper lip, forehead and nose. Female individuals in their reproductive age group are the most commonly affected. However, it can occur in male individuals and also over areas other than the face. It can be classified into epidermal, dermal or mixed type; this pattern depends on melanin distribution, as evident by Wood’s lamp examination and histopathology 1. The major etiological factors of melasma include genetic influences, chronic sun exposure, and hormonal factors including pregnancy, contraceptive pills and hormone therapy 2.
Many lines of treatment have been tried and used in melasma. These treatments include topical medications such as: hydroquinone and other bleaching drugs such as azelaic acid. Procedural treatments are used, such as microdermabrasion, and chemical peels. Lastly, LASER and light-based equipment such as Q-switched Nd: YAG laser, intense pulse light and others were all used with variable degrees of improvements. The target of all of these modalities is to reduce the formation of melanin either by direct or indirect ways 3.
Tranexamic acid is known to be a hemostatic drug. It was reported that it had a hypopigmenting effect on melasma lesions and that it also prevented the pigmentation induced by UV rays. It exerts its hemostatic function via antiplasmin activity. The intracellular release of arachidonic acid (AA) and the level of alpha-melanocyte-stimulating hormone increase as the result of plasmin activity. These two substances can eventually activate melanin synthesis. Therefore, it has been thought that the main cause of this hypopigmenting effect of this drug is its antiplasmin activity 4.
Flutamide is an antiandrogenic drug. It was speculated to have an effect in treating melasma theoretically, because a hormonal role is shown to exist, in the pathogenesis of melasma. A safe method to evaluate this effect would be to use it in a topical formula 5. Therefore, the aim of this work was to evaluate and compare the efficacy of topical tranexamic acid 5% and topical flutamide 1% in the treatment of patients with melasma.
Patients and methods
This comparative study was approved by the research ethics committee of Faculty of Medicine, Tanta University (approval code 30699/01/16). The study was carried out during the period spanning from January 2016 to May 2017. All participants provided signed informed consent before being included in the study. A total of 30 female patients who were not treated before or who had stopped treatment for at least 3 months were included in this study. Exclusion criteria were as follows: pregnant and nursing women, patients receiving oral contraceptives, patients being treated with retinoid through the last 3 weeks, patients with inflammation, infection, liver disease and patients with photosensitivity, or hypersensitivity to the components.
All the patients were subjected to: complete history taking including the following: age, skin type, duration of melasma, family history, history of predisposing and aggravating factors of melasma (UVR exposure, pregnancy, hormonal therapy, cosmetic application, associated diseases and drug intake, e.g. phenytoin, griseofulvin, phototoxic drugs, and NSAIDs).
Clinical assessment of melasma 6
The distribution of the lesions on the patients’ faces was classified into three patterns: the centrofacial pattern (where the lesions were on the forehead, cheeks, nose, upper lip, or chin), the malar pattern (where the lesions were located primarily on the cheeks and nose), and the mandibular pattern (where the lesions were on the ramus of the mandible). Wood’s light examination was performed for each patient, and the patients were classified as having epidermal type, dermal type and mixed type melasma. Facial digital photographs were obtained using a digital camera (16.2 megapixels-Canon Ixus 150, Ota, Tokyo, Japan) before and after treatment.
Scoring of the patients was performed before and after treatment according to modified melasma area and severity index (mMASI) score: mMASI score=0.3 A (f) D (f)+0.3 A (lm) D (lm)+0.3 A (rm) D (rm)+0.1 A(c) D(c). (f=forehead, lm=left malar, rm=right malar, c=chin, A=area value, D=darkness), as shown in Table 1. It was calculated by multiplying the value of the area of involvement by the severity rating for darkness, for each of the four facial areas. The range of the total score was from 0 to 24.
The formulations of the drugs used in this study were shown in Table 2. Gel-like liquid crystalline preparation containing 1% w/w flutamide was prepared by dispersing the drug in propylene glycol. This dispersion was mixed with tween 80 before addition of oleic acid with mixing. Water was gradually added to form gel-like liquid crystals, which were packed in suitable containers. Gel-like liquid crystalline preparation containing 5% w/w tranexamic acid was prepared mixing oleic acid with tween and propylene glycol. The drug solution was then added, and the weight was completed with water to produce the required formulation, which was packed as before. Preparation of the gel formulation was carried out in the Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University.
A split-face method was carried out as follows: patients were treated with 1% flutamide topical gel on the right side of the face (side A) and 5% tranexamic acid topical gel on the left side of the face (side B) every night after cleaning the face for 12 weeks. The gel formula was kept in the refrigerator during the period of treatment. Patients were seen regularly every month for clinical assessment. Sunscreen preparations with (SPF 30) or more were applied by all patients during the day. All the patients were instructed to avoid use of any other treatment of melasma during the period of this study. Any side effects observed were recorded at each treatment session and follow up visit. Each patient was asked to rate their satisfaction as either extremely satisfied, very satisfied, moderately satisfied or mildly satisfied or as no improvement 7. Measurement of the efficacy of the treatment was performed: efficacy of the treatment=(mMASI score before−mMASI score after)/mMASI score before×100 8. Follow-up for a period of 3 months was carried out for all patients to detect any recurrence.
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0 (v 16; SPSS Inc., Chicago, Illinois, USA). Qualitative data were described using number and percent. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level. The used tests were as follows: χ2-test for categorical variables to compare between different groups, Monte Carlo for correction of χ2 when more than 20% of the cells had expected count less than 5, Student’s t-test for normally quantitative variables to compare between two studied groups, Mann–Whitney test for abnormally quantitative variables to compare between two studied groups, Wilcoxon signed ranks test for abnormally quantitative variables to compare between two periods and Spearman’s coefficient to correlate between two abnormally quantitative variables.
With regard to the age of the patients, it ranged from 32.0 to 48.0 years, with a mean of 40.80±5.29 years. The duration of melasma ranged from 2.0 to 15.0 years with a mean of 8.60±3.94 years. All demographic data of the patients are shown in Table 3.
The mMASI score before treatment in side A (treated with flutamide) ranged from 0.60 to 6.0 with a mean of 3.34±1.88, and the mMASI score after treatment ranged from 0.30 to 6.0 with a mean of 2.94±1.83. There was a significant decrease in mMASI score after treatment (P=0.007) Figs 1–3. The mMASI score before treatment in side B (treated with tranexamic acid) ranged from 0.60 to 7.20 with a mean of 3.72±1.78, and the mMASI score after treatment ranged from 0.30 to 7.20 with a mean of 1.63±1.34. There was a significant decrease in mMASI score after treatment (P=0.002) Figs 4–6. On comparing between both sides, side B showed better improvement than side A, with a statistically significant decrease in mMASI score after treatment (P=0.001).
As regards patient satisfaction, in side A, two (6.7%) patients were extremely satisfied, two (6.7%) patients were very satisfied, 10 (33.3%) patients were moderately satisfied, 12 (40%) patients were mildly satisfied, and four (13.3%) patients were not satisfied. As regards side B, six (20%) patients were extremely satisfied, 14 (46.7%) patients were very satisfied, eight (26.7%) patients were moderately satisfied, and two (6.7%) patients were mildly satisfied. There was significant difference between the studied groups, as regards the patient satisfaction (P=0.017), with the better results in side B. As regards the side effects in the present study, no side effects were reported in all patients when using both drugs. Moreover, no recurrence occurred during the period of follow-up, which continued for 3 months after stoppage of treatment.
There was no significant relation between the efficacy of treatment and pattern of melasma, family history, skin type or type according to Wood’s light as shown in Table 4. Furthermore, there were no statistically significant correlations between the efficacy of treatment and either age or duration of melasma with P value 0.328 and 0.756, respectively.
Melasma is a common acquired disorder of hyperpigmentation that occurs usually in female individuals (> 90% of cases). Although melasma is a benign condition, it can cause severe psychological distress, and social and emotional problems. Moreover, it was reported to have a significant impact on quality of life. There is no reported effective or specific treatment. Usually, in resistant cases, it is better to use combinations of modalities, to augment the effect of therapy 9. Therefore, the aim of this study was to evaluate the efficacy of topical tranexamic acid gel for treatment of melasma and to compare it with topical flutamide gel.
In our study, all patients were female individuals. This might be due to the fact that, female individuals are usually more aware about their image, and they complain more and earlier than men. This was in agreement with Kristlova 10 and Katsambas et al.11 These results disagreed with Sarkar et al.12 They found that 25.83% of Indian melasma patients were male individuals. This was due to UV exposure, and because of use of vegetable oils after bath, which may help in appearance of pigmentation in male individuals.
With regard to the age of the studied patients, it ranged from 30 to 48 years. Melasma predominantly appeared in female individuals during the reproductive age and in those who used to take estrogen-progesterone contraceptive methods. This was in agreement with Achar and Rathi 13, who stated that melasma is more common in adult women in childbearing age, and the age of onset is between 30 and 55 years.
The current study showed that the history of pregnancy was found in 17 (56.6%) patients. History of UVR exposure was found in 16 (53.3%) patients. These results were in agreement with Handel et al.14, as they reported history of pregnancy in 51%, followed by UVR exposure in 49%. History of UVR exposure could be explained in workers or housewives and could be an indicator of sunlight exposure. Moreover, socioeconomic standard of the patients could also be a factor, as most of them are farmers, poor and not oriented to using sunscreens. Moin et al.15 disagreed with these results; they stated that UVR exposure is a major triggering predisposing factor in development of melasma. In this study, family history was found in 14 (46.6%) patients. Achar and Rathi 13 found positive family history in 33.33% of patients; therefore, the genetic factor could be considered asimportant. This was in accordance with the current results.
As regards the pattern of melasma in this study, the malar pattern was the predominant pattern, followed by the centrofacial pattern. These results were concomitant with Grovers and Reddu 16 In contrast to this finding, Ilknur et al.17 stated that the centrofacial pattern was the predominant pattern found in (63–83%) of cases.
With regard to the Fitzpatrick skin phototypes, patients in this study were of darker skin types (types III, IV, and V). The most common type was skin phototype IV and III, followed by V and lastly II. These results were in agreement with Pawar et al.18 and Handel et al.14 They reported that melasma is more common in people with darker skin (type IV−VI skin).
With regard to the type, according to Wood’s light examination in the present study, the epidermal type was the most predominant one, followed by mixed type and lastly the dermal type; these results were in consistence with Hurley et al.19 and Javaheri et al.20 They reported that mixed and epidermal types were found in 96% of patients, while the dermal type was found only in 4%.
With regard to treatment with 1% Flutamide topical gel on the right side (side A) of the face, there was a significant decrease in mMASI score after treatment than before treatment. These results were in agreement with Elbuluk et al.21, who used 1% flutamide cream daily for 12 weeks, and they found a statistically significant decrease in mean MASI score after treatment. Moreover, Adalatkhah et al.5 used 1% flutamide cream and 4% hydroquinone cream daily for 12 weeks, and they reported that both the hydroquinone and flutamide creams were effective in treating the melasma. When using both MASI scale score and the patient satisfaction score, they stated that flutamide had a greater efficacy than hydroquinone in treating melasma.
Flutamide has been used before for treatment of hirsutism, acne and hair loss. It was used either in its topical or oral form. It had very good promising results in human and animal studies. The exact mechanism of action of flutamide on melasma was very difficult to elucidate. Theoretically, there was evidence that a potential relationship existed between androgenic-related conditions such as acne, polycystic ovarian disease, hirsutism and melasma 22. The role of flutamide in melasma, depends on decreasing the alpha-melanocyte-stimulating hormone, or cyclic adenosine monophosphate-elevating agents, which affect/s the melanin synthesis 23. Many adverse effects were reported on using the systemic drug. However, the use of the topical form is much more attractive for dermatologists, because there are relatively mild or even no systemic side effects. Hence, topical flutamide would be safer compared with its oral form, as regards severe side effects 24.
As regards treatment with 5% tranexamic acid topical gel on the left side of the face side (B), there was a statistically significant decrease in mMASI score after treatment than before treatment. These results were in agreement with Lee et al.25, who used intradermal injection of 0.05 ml of tranexamic acid 4 mg/ml in patients with melasma, weekly for 12 weeks. They reported a significance decrease in mean MASI score. Moreover, Cho et al.26 studied the role of oral tranexamic acid 500 mg/day in melasma patients treated with low fluence QS Nd:YAG laser and IPL, and they revealed that the mean modified MASI score decreased after the last laser treatment. The current results were similar to the previous two studies, but with the benefit of being safer with no side effects, such as systemic and intralesional forms. Furthermore, topical tranexamic was cheaper than expensive laser or IPL sessions. Moreover, Ebrahimi et al.27 studied the role of topical 3% tranexamic acid on one side of the face in patients with melasma daily for 12 weeks, and they reported a significanct decrease in mean MASI score, as the present study.
Tranexamic acid acts as a plasmin inhibitor. It interferes with the structure of the plasminogen molecule, preventing its binding to the lysine-binding site, leading to inhibition of plasminogen activator (PA) from converting plasminogen to plasmin 25. UV irradiation stimulates the synthesis of PA and plasmin activity in cultured keratinocyte, increasing phospholipase A2. It induces the production of AA from membrane phospholipids, which is a precursor to prostaglandin E2 (PGE2) and leukotriens (LK), which can subsequently lead to melanogenesis. Tranexamic acid was speculated to inhibit the activity of plasmin in keratinocytes induced by UV. It prevents the binding of plasminogen to the keratinocytes, resulting in less free AA and a diminished ability to produce PGs, and this lowers the melanocyte tyrosinase activity 28. Plasmin also participates in the release of basic fibroblast growth factor (bFGF), which is a powerful melanocyte growth factor. Therefore, inhibition of plasmin by tranexamic acid leads to inhibition of bFGF and growth of melanocytes. Moreover, tranexamic acid suppresses angiogenesis and inhibits new vessel formation stimulated by bFGF, which contribute to development of melasma 29.
To our best knowledge, there are no previous published data comparing between the efficacy of topical tranexamic acid 5% and topical Flutamide 1% in treatment of patients with melasma. It was found that side B (treated with tranexamic acid) had better results than side A (treated with flutamide), with a statistically significant decrease in mMASI score, when compared with side A. Moreover, on evaluation of patient satisfaction in the present study, side B showed higher patient satisfaction than side A, with a significant difference between the two sides with the best results in side B. With regard to the side effects in the present study, no side effects were reported in all patients in both sides, revealing the safety of the used drugs. Furthermore, no recurrence was reported in the follow-up period in both sides.
From this study we concluded that both topical tranexamic acid and flutamide are new, effective, cheap and safe therapeutic modalities for the treatment of melasma, with no side effects. However, the improvement was better with the use of tranexamic acid. Further studies should be carried out on a larger number of patients and for a longer period of follow-up to assess the possibility of recurrence.
Conflicts of interest
There are no conflicts of interest.
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