Topical Silymarin Versus Hydroquinone in the Treatment of Melasma: a Comparative Study

Received: 26 April 2018 | Accepted: 19 July 2018 DOI: 10.1111/jocd.12769

ORIGINAL CONTRIBUTION

Topical silymarin versus hydroquinone in the treatment of melasma: A comparative study

Ahmad Nofal MD1 | Al‐Shimaa M. Ibrahim MD1 | Eman Nofal MD1 | Noura Gamal PhD2 | Shimaa Osman MB, BCH1

1Dermatology Department, Faculty of Medicine, Zagazig University, Zagazig, Summary Egypt Background: Melasma is a highly prevalent hyperpigmentation disorder with a 2Pharmaceutics and Industrial Pharmacy high relapsing rate and a negative impact on the psychological state of the Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt affected patients. The exact pathogenesis of melasma is not completely eluci- dated; however, ultraviolet induced oxidative stress has an important role in its Correspondence Ahmad Nofal, Dermatology Department, pathogenesis. Silymarin, antioxidant drug, reduces the harmful effects of solar Faculty of Medicine, Zagazig University, ultraviolet radiation such as inflammation, immune responses, DNA damage, and Zagazig, Egypt. Email: [email protected] pigmentation. Objectives: To assess the efficacy and safety of topical silymarin with different concentrations (0.7% and 1.4%) versus hydroquinone 4% in the treatment of melasma. Methods: Forty‐two adult female patients with melasma were assigned to three equal groups each containing 14 patients; group1 was treated by silymarin 0.7% cream, group 2 was treated by silymarin 1.4% cream and group 3 was treated by hydroquinone 4% cream. The duration of treatment was 3 months. Results: MASI score was significantly reduced in all groups at the end of third month; however, there were no significant differences in the therapeutic response between the three studied groups. No side effects were recorded with silymarin, while hydroquinone was associated with significant adverse effects. Conclusions: Silymarin cream might serve as an effective and safe treatment modality for melasma.

KEYWORDS hydroquinone, melasma, silymarin

1 | INTRODUCTION Hypermelanosis caused by UV radiation might be attributed to increasing melanocyte activity and peroxidation of cell membrane Melasma, the commonest acquired hyperpigmentation in women, lipids with production of free radicals that stimulate excess melanin affects mainly the ultraviolet (UV) exposed areas particularly fore- production. It has been suggested that oxidative stress plays an head, cheeks, temples, and upper lip. It has a negative impact on the important role in the pathogenesis of melasma. Different anti‐oxi- psychological state and quality of life of the affected patients. Multi- dants such as vitamin E, niacinamide, and vitamin C have been used ple factors are implicated in the pathogenesis of melasma; however, in the treatment of melasma especially due to their inhibitory effect the definite underlying mechanisms are not yet completely estab- on free radicals, which trigger melanin synthesis.4–6 lished. Ultraviolet exposure is one of the main etiological factors, Silymarin is derived from the milk thistle plant “Silybum mari- besides genetic and hormonal factors.1–3 anum.” Silibinin, the main component of silymarin, has been found

| J Cosmet Dermatol. 2018;1–8. wileyonlinelibrary.com/journal/jocd © 2018 Wiley Periodicals, Inc. 1 2 | NOFAL ET AL. to have antioxidant properties. It decreases the hazardous effects of Therapeutic response was assessed by comparing MASI score solar ultraviolet radiation and significantly prevents melanin produc- throughout the 3‐month treatment course. It was considered excel- tion in a dose‐dependent manner without effect on cell viability.7,8 lent if MASI score decreased by >75%, good if MASI score Hydroquinone (HQ) is the most popular and most extensively decreased by 50%‐75%, medium if MASI score decreased by 25%‐ studied medication in the management of melasma. It inhibits 50%, and poor if MASI score decreased by <25%. melanogenesis by inhibiting tyrosinase enzyme, affects the forma- Therapeutic response was also assessed by measurement of tion, melanization, and degradation of melanosomes and modulates patient satisfaction: grade 0 = not satisfied, grade 1 = partially satis- the membranous structures of melanocytes, causing necrosis of fied, grade 2 = greatly but not completely satisfied, grade 3 = com- whole melanocytes. Hydroquinone is, however, associated with fre- pletely satisfied. quent adverse effects that stimulate the research for other agents Adverse effects of the three treatment modalities were evaluated with equal efficacy and more safety.9,10 Herein, we evaluate the effi- at each visit, and follow‐up was performed every month for cacy and safety of topical silymarin, at different concentrations, ver- 6 months after the end of the treatment course to detect any recur- sus hydroquinone 4% in the treatment of melasma. rence of melasma.

2 | PATIENTS AND METHODS 2.3 | Statistical analysis

Data were checked, entered, and analyzed using SPSS (version 19). 2.1 | Patients Data were represented as mean ± SD for quantitative variables. Num- Forty‐two adult female patients with melasma of different durations, ber and percentage were used for categorical variables. The one‐way severities, patterns and types were included in the study. Exclusion ANOVA test, chi‐square test, and paired t test were used to assess the criteria included pregnancy, breast feeding, coexistence of diseases results. P values <0.05 was considered statistically significant. associated with hyperpigmentation such as Addison disease, con- comitant use of drugs that may induce hyperpigmentation such as 3 | RESULTS oral contraceptives, and treatment of melasma within the last month before enrolment. The study has been approved by the local Institu- All the patients completed the study. Baseline characteristics of the tional Review Board, and an informed consent was taken from each studied patients are shown in Table 1.There were no statistical sig- patient before participation in the study. nificant differences between the three studied groups in the baseline All patients were subjected to through history taking, including characteristics, except for family history that was statistically higher onset and duration of melasma, family history, relation to pregnancy, in group 2 as compared to group 1 and 3. relation to sun exposure, history of systemic diseases, and previous treatments. Complete dermatological examination was also performed 4 | ASSESSMENT OF THERAPEUTIC to assess Fitzpatrick skin type, pattern of melasma (centro‐facial, RESPONSE malar, or mandibular), melasma type (epidermal, dermal, or mixed) and severity as assessed by melasma area and severity index score (MASI 4.1 | A: MASI score Score).4 The severity of melasma was divided according to MASI score into mild (1‐16), moderate (>16‐32), and severe (>32‐48). 4.1.1 | In group 1 (silymarin 0.7% cream)

At baseline, the mean of MASI score was 18.56 ± 5.58, after 2.2 | Methods 1 month it decreased to 13.94 ± 4.92, after 2 months it became The patients were divided into 3 equal groups, each contained 14 12.62 ± 4.76, at the end of treatment it became 10.96 ± 4.48%, and patients. Group 1 received silymarin 0.7% cream, group 2 received % of reduction in MASI score after treatment was 39.21 ± 20.65. silymarin 1.4% cream and group 3 received hydroquinone 4% cream. Silymarin was applied twice daily, while HQ was used once daily at 4.1.2 | In group 2 (silymarin 1.4% cream) night. The duration of treatment was 3 months in the 3 studied groups. At baseline, the mean of MASI score was 21.75 ± 8.47, after Silymarin cream was prepared in the Faculty of Pharmacy, Zaga- 1 month it decreased to 17.39 ± 8.07, after 2 months it became zig University, Egypt according to the following formulation: stearic 15.6 ± 7.92, at the end of treatment it became 14.88 ± 7.79%, and acid 15 g, glycerin 5 g, KOH 0.72 g, H2O 79 g, sodium benzoate % of reduction in MASI score after treatment was 33.84 ± 15.61. (0.1%), and Tween‐80 (1%). Silymarin was added as 0.7% or 1.4%. All patients were advised to avoid excessive sun exposure and to 4.1.3 | In group 3 (hydroquinone 4% cream) apply a broad spectrum sunscreen with a sun protection factor of at least 50. Digital color photographs were taking at baseline and every At baseline, the mean of MASI score was 16.64 ± 9.0, after 2 weeks during treatment course. 1 month it decreased to 12.25 ± 6.94, after 2 months it became NOFAL ET AL. | 3

TABLE 1 Baseline characteristics of the studied patients

Group 1 Group 2 Group 3 Variable Silymarin 0.7% (n = 14) Silymarin 1.4% (n = 14) Hydroquinone 4% (n = 14) Test P Age: (year) F Mean ± SD 38 ± 5.86 40.07 ± 7.48 37.43 ± 6.39 0.54 Range 30−50 30−52 28−50 0.62 NS Duration: (year) K Mean ± SD 5.02 ± 3.54 7.70 ± 5.8 4.56 ± 4 3.83 0.15 Range 4 month to 12 year 1−20 years 3 month to 16 years NS Variable No % No % No % χ2 P Pregnancy No 8 57.1 11 78.6 6 42.9 3.76 0.15 Yes 6 42.9 3 21.4 8 57.1 NS Sun exposure No 6 42.9 8 57.1 7 50 0.19 0.91 Yes 8 57.1 6 42.9 7 50 NS Family history No 11 78.6 6 42.9 13 92.9 9.1 0.01* Yes 3 21.4 8* 57.1 1 7.1 Previous therapy No 8 57.1 5 35.7 11 78.6 5.25 0.07 Yes 6 42.9 9 64.3 3 21.4 NS Skin type III 3 21.4 5 35.7 5 35.7 2.69 0.61 IV 10 71.4 9 64.3 9 64.3 NS V 1 7.2 0 0 0 0 Melasma type Dermal 1 7.1 2 14.3 0 0 5.92 0.21 Epidermal 11 78.6 9 64.3 14 100 NS Mixed 2 14.3 3 21.4 0 0 Pattern Centro‐facial 10 71.4 12 85.7 10 71.4 2.4 0.30 Malar 4 28.6 2 14.3 4 28.6 NS Severity Mild 6 42.9 4 28.6 9 64.3 5.6 0.23 Moderate 8 57.1 8 57.1 4 28.6 NS Severe 0 0 2 14.3 1 7.1

K: Kruskal‐Wallis test; χ2: Chi‐square test; F: ANOVA test; NS, Nonsignificant; SD: Standard deviation. *Significant.

10.82 ± 7.10, at the end of treatment it became 8.81 ± 5.68% 4.2 | B: Patient satisfaction and % of reduction in MASI score after treatment was 46.75 ± 22.83. There were no statistical significant differences between the three There was a statistically significant decrease in MASI score studied groups in patient satisfaction (Table 4). within the same group. Although the percent of reduction in MASI score was slightly higher in hydroquinone group, no statisti- 4.2.1 | Relationship between therapeutic response cally significant difference in MASI score between the three stud- and different clinical variables ied groups was found (Table 2). Assessment of the therapeutic response at different stages of treatment is shown in Table 3 and There was no statistical significant relationship between the thera- Figures 1–3. peutic response and the different clinical variables in all groups. 4 | NOFAL ET AL.

TABLE 2 MASI score among the studied groups

Group 1 Group 2 Group 3 MASI score Silymarin 0.7% Silymarin 1.4% Hydroquinone 4% KP At Baseline Mean ± SD 18.56 ± 5.58 21.75 ± 8.47 16.64 ± 9.02 2.52 Median 17.85 20 14.25 0.28 Range 8.4−27.6 9−35.8 5−32.1 NS After 1 month Mean ± SD 13.94 ± 4.92 17.39 ± 8.07 12.25 ± 6.94 3.25 Median 12.9 16.4 11.7 0.20 Range 8.2−23.4 6.8−32.9 3.8−23 NS After 2 months Mean ± SD 12.62 ± 4.76 15.6 ± 7.92 10.82 ± 7.10 2.42 Median 11.95 12.8 11.1 0.30 Range 7.7−23 6.3−30.2 1.8−23 NS After 3 months Mean ± SD 10.96 ± 4.48 14.88 ± 7.79 8.81 ± 5.68 3.03 Median 10.9 11.35 9.15 0.07 Range 4.8−19.6 6.3−28.6 1.8−21 NS P <0.001** <0.001** <0.001** % of reduction in MASI score Mean ± SD 39.21 ± 20.65 33.84 ± 15.61 46.75 ± 22.83 3.03 0.22 Median 36.11 34.24 39.74 NS Range 2.38−77.36 7.35−64.46 18.37−82

SD: Standard deviation; K: Kruskal‐Wallis test; NS, Nonsignificant (P > 0.05). **Highly significant (P < 0.01).

TABLE 3 Therapeutic response among the studied groups

Group 1 Group 2 Group 3 Silymarin 0.7% Silymarin 1.4% Hydroquinone 4%

Therapeutic response No % No % No % χ2 P After 1 month Poor 9 64.3 9 64.3 9 64.3 2.5 0.65 Medium 4 28.6 5 35.7 3 21.4 Good 1 7.1 0 0 2 14.3 NS After 2 months Poor 7 50 5 35.7 7 50 9.52 0.15 Medium 6 42.9 8 57.1 2 14.3 Good 1 7.1 1 7.1 3 21.4 NS Excellent 0 0 0 0 2 14.3 After 3 months Poor 3 21.4 5 35.7 3 21.4 5.23 0.52 Medium 6 42.9 7 50 5 35.7 Good 4 28.6 2 14.3 3 21.4 NS Excellent 1 7.1 0 0 3 21.4 P <0.001** 0.02*<0.001**

χ2: Chi‐square test; NS: Nonsignificant. *Significant. **Highly significant NOFAL ET AL. | 5

(A) (B)

FIGURE 1 Moderate malar melasma showing excellent response to silymarin 0.7%. A, Right side of the face before treatment. B, After treatment. C, Left side of the face before treatment. D, After treatment

(A) (B)

FIGURE 2 Moderate malar melasma showing good response to silymarin 1.4%. A, Right check before treatment, B, After treatment. C, Left check before treatment. D, After treatment 6 | NOFAL ET AL.

(A) 4.2.3 | Follow up

Recurrence of melasma was observed in 1 patient (7.14%) in group 1, 1 patient (7.14%) in group 2, and 3 patients (21.4%) in group 3 after the 6‐month follow‐up period.

5 | DISCUSSION

Melasma is a highly prevalent hypermelanotic disorder in women although it can occur in men. It is often difficult to treat may be refractory to different therapeutic modalities and is commonly associated with a high relapsing rate. Principles of therapy include protection from UV rays, inhibition of melanocyte activity and melanin synthesis, and the disruption and removal of melanin granules.8,11 Topical therapy remains the mainstay of melasma treatment, with (B) hydroquinone being the most popular and extensively studied agent. In recent years, however, studies have shifted away from hydroquinone monotherapy to search for substances equal in efficacy but superior in safety. The epitome of a depigmenting agent should pro- vide powerful, quick, yet selective lightening on the hyperactive melanocytes. Resultant elimination of unwanted pigment must be lasting, with no undesirable side effects. In spite of the presence of many topical therapeutic options, the ideal depigmenting agent has yet to be found.12 This study was conducted to evaluate and compare the efficacy and safety of silymarin with two different concentrations (0.7% and 1.4%) versus the standard hydroquinone 4% in the treatment of melasma. To the best of our knowledge, this is the first study that com- pares these two different agents in the management of melasma. FIGURE 3 Moderate centro‐facial melasma showing excellent The present study revealed promising efficacy of topical silymarin response to hydroquinone. Note the erythema associated with the (0.7% and 1.4%) in the treatment of melasma. The severity of mel- use of hydroquinone. A, Before treatment. B, After treatment asma, as evaluated by MASI score, was significantly reduced after treatment with silymarin cream in both groups. Although the concentration of silymarin in group 2 (1.4%) was double the concentra- 4.2.2 | Adverse Effects tion in group 1 (0.7%), there was no statistical significant difference There was a statistically significant difference between HQ and sily- in the therapeutic response between both groups. This indicates that marin groups in the reported adverse effects. HQ was associated silymarin at low concentration might be better than the higher con- with erythema in 10 patients (71.4%), burning in 10 patients (71.4%), centrations in terms of cost and adverse effects. scaling in 10 patients (71.4%), while no side effects were detected in These results came in agreement with Elfar and EL‐Maghraby13 both groups of silymarin. who compared the efficacy of silymarin cream (14 mg/mL) versus

TABLE 4 Patient satisfaction among the studied groups

Group 1 Group 2 Group 3 Silymarin 0.7% Silymarin 1.4% Hydroquinone 0.4% (n = 14) (n = 14) (n = 14)

Variable No % No % No % χ2 P Satisfaction 0 1 7.1 1 7.1 0 0 4.88 0.56 1 3 21.4 4 28.6 1 7.1 NS 2 4 28.6 4 28.6 8 57.1 3 6 42.9 5 35.7 5 35.7

χ2: Chi‐square test; NS: Nonsignificant. NOFAL ET AL. | 7 intradermal injection of tranexamic acid and glycolic acid peeling in The absence of adverse effects in the patients treated with sily- the treatment of melasma. Their study revealed that the highest effi- marin represents an important advantage of silymarin over the con- cacy was observed in the group treated with glycolic acid peeling ventional hydroquinone that is commonly associated with the followed by silymarin group, and the least efficacy was reported in aforementioned adverse effects. This indicates that silymarin might the group treated with intradermal injection of tranexamic acid. serve as an effective and safe modality for the treatment of mel- Similarly, the results of the present study were in accordance asma. with those demonstrated by Altaei14 who reported significant Recurrence of melasma was reported in 1 patient (7.14%) in improvement of melasma after treatment with silymarin (7 and group 1 (silymarin 0.7%), in 1 patient (7.14%) in group 2 (silymarin 14 mg/mL). The author in this study used silymarin versus placebo, 1.4%), and in 3 patients (21.4%) in group 3 (hydroquinone 4% group) the duration of the study was 1 month only and no follow‐up was after of the 6‐month follow‐up period. These results suggest that performed. In our study, silymarin was used versus hydroquinone silymarin may decrease the recurrence rate of melasma better than 4%, the duration of the study was 3 months and follow‐up was per- hydroquinone. Besides its high safety profile, this finding represents formed every month for 6 months. another advantage of silymarin over hydroquinone. However, The exact mode of action of silymarin is not yet completely eluci- because of the small number of the studied patients and the short‐ dated. Silibinin, the main component of silymarin, has powerful antiox- term follow‐up, it is early to make a definite conclusion or recom- idant and photoprotective effects. It minimizes the hazardous effects mendation in this respect. of UV radiation such as oxidative stress, inflammation, edema, ery- In conclusion, topical silymarin is an effective and safe treatment thema, DNA damage, and immune responses. Silymarin can also modality for melasma and may represent a promising alternative to reduce melanin production by its antioxidant effect and inhibition of L‐ conventional hydroquinone. Longer duration of therapy is recom- dopa oxidation activity of tyrosinase. In addition, it has been found mended for better results. Further studies on a large scale of patients that silymarin decreases the expression of tyrosinase protein.7,8 and long‐term follow‐up are recommended to confirm these results. Hydroquinone has been proven as an effective treatment for melasma in a large number of previous studies.15–21 This came in agreement with the results of the present study that revealed signifi- CONFLICT OF INTEREST cant reduction of the severity of melasma after treatment with None declared. hydroquinone for 3 months. There was no statistically significant difference in the therapeutic response between silymarin‐treated groups and hydroquinone group. This finding strongly suggests that ORCID silymarin might serve as a promising alternative to hydroquinone. There was no statistical significant relationship between the ther- Ahmad Nofal http://orcid.org/0000-0002-5899-7195 apeutic response in the three studied groups and the different clini- Eman Nofal http://orcid.org/0000-0001-9305-2480 cal variables including melasma characteristics such as type, pattern, severity and duration, and patient characteristics such as age, skin type, sun exposure, family history, and pregnancy. These results dis- REFERENCES ‐ 13 agree with Elfar and EL Maghraby who reported an inverse rela- 1. Handel AC, Miot LD, Miot HA. Melasma: a clinical and epidemiologi- tionship of the therapeutic response of silymarin with age, duration cal review. An Bras Dermatol. 2014;89:771‐782. of melasma, skin phototype, and melasma type. Differences in the 2. Pawaskar MD, Parikh P, Markowski T, McMichael AJ, Feldman SR, Balkrishnan R. 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