Hamadi S. et al., Journal of Arab Universities for Basic and Applied Sciences, Vol.8, 2009, 30-42
The Role of Topical and Oral Melatonin in Management of Melasma Patients
Salim A. Hamadi1, Mohammed Mahmmod Mohammed2, Ashwaq Nejmelden Aljaf3 & Ali Abdulrazak4
1 Faculty of pharmacy & Medical Sciences, Petra University, Amman, Jordan, 2 College of pharmacy, University of Almustansiryah, Baghdad, Iraq, 3 College of pharmacy, University of Baghdad, Baghdad, Iraq, 4 Alkarama teaching hospital, Baghdad, Iraq
Dr. Salim A. Hamadi, Faculty of pharmacy & Medical Sciences, Petra University,
P.O. Box: 961343, Amman, Jordan
E-mail:
ABSTRACT
This novel study was designed to evaluate the possible effects of topically formulated melatonin cream alone or in combination with sunscreen and oral melatonin for the management of melasma patients in comparison with hydroquinone as a standard therapy. This study carried out in the dermatology department at the AL-Karama teaching hospital, Baghdad, Iraq. In a double blind manner, this preliminary clinical study was performed on 36 patients with epidermal melasma and 10 healthy subjects as control. They were diagnosed as having melasma and they were under dermatologist supervision during the entire period of treatment. The patients were allocated into four groups (A, B, C, and D), and treated with topical melatonin only, topical melatonin and sunscreen, topical and oral melatonin, and 4% hydroquinone cream, respectively for a period of 90 days followed by 30 days treatment with placebo. The severity of melasma was evaluated using the Melasma Area & Severity Index (MASI) before starting treatment and after each 15 days for 120 days. To evaluate the oxidative stress status, malondialdehyde (MDA) and glutathione (GSH) levels in plasma were measured before starting treatment and after 45, 90, and 120 days of treatment.
At the end of treatment period (90 days); all melasma patients demonstrated significant reduction in MASI score in different levels. In addition, the plasma MDA levels were decreased and plasma GSH levels were increased in different scales after 90 days of treatment. The overall results of this preliminary study suggested that topical melatonin could be used as a hypopigmenting agent in treatment of melasma, and this effect is augmented by the oral administration of the drug and the use of sunscreen, possibly by its antioxidant activity or by other mechanisms unrelated to antioxidant effect.
Key ward: Melatonin, Melasma, antioxidant,
INTRODUCTION
Melasma is one of the most common causes of acquired, symmetric hypermelanosis of the face characterized by irregular light- to gray-brown patches on sun-exposed areas (Grimes, 1995). The most common sites of involvement are the cheeks, forehead, upper lip, nose, chin, and occasionally the forearms (Sivayathorn, 1995). Melasma seen mainly in women at any time during the years of reproductive activity, it may be seen in men, and it tends to occur more often in dark skinned individuals ( Bleehen et al., 1992).
Melasma usually distributed as one of three clinical patterns; centrofacial, malar, and mandibular ( Sanchez et al., 1981). Melasma can also be divided into three types according to Wood’s light examination of the skin (Grimes, 1995). The epidermal type has increased melanin predominantly in the basal and suprabasal epidermis with accentuation by Wood’s lamp. The dermal type has melanin-laden macrophages in a perivascular distribution in superficial and deep dermis, with no Wood’s lamp accentuation. The mixed type has both elements and appears as a deep brown color, with Wood’s lamp accentuation of only the epidermal component (Pathak, 1986).
Various factors and causes are responsible for the pathogenesis of melasma, but UV exposure, genetic influences, and hormonal changes are the most commonly cited etiologic factors (Pathak, 1986). Many therapeutic agents are available but are often unsatisfactory, including sunscreen and hypopigmenting agents like hydroquinone, Tretinoin, and Azelaic acid. The most commonly used hypopigmenting agent for the treatment of melasma is hydroquinone, which reduces the conversion of L-dopa to melanin by inhibiting the enzyme tyrosinase, hydroquinone used alone or in combination with other therapies, such as tretinoin, topical corticosteroids, and/or superficial peeling agents( Balina & Graup, 1991),(Guevara & Pandya, 2001),( Hurly et al., 2002). Recently, it has been demonstrated that the generation of oxygen free radicals in response of skin exposure to the sun light is involved in the pathogenesis of melasma. The administration of antioxidants may decrease the effects of oxidative damage induced by UV radiation on skin pigmentation (Huh et al., 2003).
Melatonin is a hormone with multiple functions in human, synthesized and secreted by the pineal gland in response to changes in the darkness and light environment of the human (Brzezinski,1997). It is a powerful antioxidant and the most potent free radical scavenger known (Sener et al., 2003). A distinct dose-response relationship was observed between the topical use of melatonin and the degree of UV-induced damage, melatonin enhances the ability of the skin to repair itself from free radical-induced damage during day light hours (Ryoo et al., 2001). Melatonin, vitamin C, and vitamin E, as antioxidants, may function in melasma by reducing UV-induced free radicals. We chose melatonin not only due to its powerful antioxidant activity, but also for its effect on the hormones that involved in the pathogenesis of melasma, like melanocytes stimulating hormone (MSH), estrogen, and progesterone (Snell & Beschitz, 1960). This study was performed to evaluate the possible effects of melatonin (alone or in combination with sunscreen) in the improvement of melasma patients, and comparing these hypopigmentic effects with those produced by hydroquinone.
MATERIALS AND METHODS
This preliminary clinical study was carried out on 46 subjects, 36 patients with melasma (22 females and 14 males) aged (17-38) years with a mean of age (26.3 ± 5.2) years, and have a disease duration of (4.6 ±3.2) years. The patients included in this study were diagnosed as having epidermal type of melasma, were free from apparent other diseases. The patients were under dermatologist supervision during the period of treatment. All patients were instructed to quit any other depigmenting and sun-protecting medications at least two weeks before starting the treatment. The patients were allocated into four groups and according to the treatment schedule indicated, as follows:
Group A: Include 10 patients (3 males and 7 females) treated with 5% melatonin cream prepared for this purpose in a two daily doses at afternoon and night.
Group B: Include 10 patients (4 males and 6 females) treated with topical broad-spectrum sunscreen (SPF 50) in a single morning dose, and with 5% melatonin cream in two daily doses at afternoon and night.
Group C: Include 10 patients (4 males and 6 females) treated with 5% melatonin cream in two daily doses at afternoon and night and with 3mg/day melatonin tablet in a single daily dose at bedtime.
Group D: Include 6 patients (3 males and 3 females) treated with 4% hydroquinone cream in two daily doses at afternoon and night.
Ten healthy subjects (2 males and 8 females) with the same age range as that of patients (26.5-35) years with a mean of age (29±3.7) years were selected and served as controls for comparison. In a double blind technique, all patients were received these treatments for three months, and then received a placebo formula for one month.
Melasma severity evaluated according to the area involved, color, and homogeneity of melasma using the Melasma Area and Severity Index (MASI) introduced by Kimbrough-Green et al., 1994. In this system the face is divided into four areas and each area represent a specified percentage of the whole face, as follow:
Forehead = 30%, right malar = 30%, left malar = 30%, and chin = 10%.
The MSAI score was calculated by the following equation:
MASI = 0.3 (DF + HF) AF + 0.3 (DMR + HMR) AMR + 0.3 (DML + HML) AML + 0.1 (DC + HC) AC.
Where D = darkness and H = homogeneity, A = area, F = forehead, MR = right malar, ML = left malar and C = chin
The values 0.3, 0.3, 0.3 and 0.1 represent forehead, right malar, left malar and chin percentages of total facial area respectively (14). MASI score was measured before treatment as base line, and every 15 days for 120 days (four months).
To evaluate the roles of oxidative stress in the etiology and pathogenesis and the roles of antioxidants in treatment of melasma, fresh blood samples were used for malondialdehyde (MDA) (as a marker of lipid peroxidation), and glutathione (GSH) (as a marker of the antioxidant system) measurements in plasma. Blood samples were collected from patients of groups A, B, C, D, and control group by vein puncture, the first sample was drawn before treatment (as baseline samples), after 45, and 90 days of the treatment, and then after 30 days of placebo treatment to evaluate the change in the studied parameters.
The student’s t-test and analysis of variance ANOVA were used to examine the degree of significance, and P value less than 0.05 was considered significant, and P value less than 0.01 was considered highly significant.
RESULTS
The result of this study revealed that all melasma patients in the four groups that treated with different treatment regimens demonstrated significant reduction in MASI score in comparison to baseline after 90 days of the treatment. However, monitoring the follow up period with placebo treatment (for 30 days) showed that group A patients demonstrated non-significant reduction in MASI score in comparison to the baseline value (P>0.05), while group B, C, and D patients demonstrated increased MASI score over that achieved at day 90 which was still significantly different in comparison to baseline value (P<0.05) as shown in Fig. 1.
Fig. 1: Effect of treatment with topical melatonin (group A), topical melatonin-sunscreen (group B), topical melatonin-oral melatonin (group C) and topical 4% hydroquinone cream (group D) on MASI score.
· = Significantly different with respect to baseline value, P<0.05.
When the effects of the four strategies of treatments (A, B, C and D) were compared at the end of treatment period (90 days); patients in groups B, C and D demonstrated significant reduction in MASI score (31.11%, 28.4% and 37.23% respectively) in comparison to that elicited by treatment with topical melatonin only, group A (13.83%) (P<0.05) as shown in Fig. 2..
Moreover, no significant difference was noticed in the effect produced by treatment with topical melatonin-sunscreen (group B) or treatment with topical melatonin-oral melatonin (group C) on percent reduction in MASI score (P>0.05) as shown in Fig. 2. This figure also revealed that the effect of 4% hydroquinone cream was significant and potent in improving MASI score than therapy received by group B and C (P<0.05). In addition, hydroquinone is shown to be the least one exhibited a relapse phenomenon among all other therapies.
Figure 2. Effect of treatment with topical melatonin (A), topical melatonin-sunscreen (group B), topical melatonin-oral melatonin (group C) and topical 4% hydroquinone cream (group D) on MASI score.
- Data are expressed as mean ± SEM.
- Treatment with placebo starts after ending of 90 days of different treatment regimens.
- Non-identical superscripts (a, b, c) among different groups are consider significantly different, P<0.05.
- P<0.05 with respect to day 90.
At the end of 90 days treatment, the results demonstrated highly significant reduction in MDA level in comparison to the baseline level (P<0.01) for group A, B, and C patients. While group D patients that treated with topical hydroquinone showed no significant reduction in the level of MDA during 90 days of treatment (P>0.05) as shown Fig. 3. However, stopping the four treatment regimens and continue treatment with placebo for 30 days strongly attenuated the effect produced by these four treatment regimens and less reduction in MDA was reported in all group which is not significantly different from the baseline level (P>0.05) as demonstrated in Fig. 3. When the effect of the four treatment regimens is compared at the end of day 90, significant differences in the level of MDA were reported in groups B, C and D (23.37%, 28.15% and 5.25% respectively) from that in group A (14.27%) (P<0.05). Moreover, MDA level in group C is highly reduced but not significantly different from that in group B as demonstrated in Fig. 4.
Another oxidative stress marker measured is plasma GSH, after 90 days treatment, significant elevation in the level of GSH is reported when topical melatonin is given alone (group A), or with sunscreen (group B), or with oral melatonin (group C) in comparison to baseline level (P<0.05).
Fig 3: Effect of treatment with topical melatonin (group A), topical melatonin-sunscreen (group B), topical melatonin-oral melatonin (group C) and topical 4% hydroquinone cream (group D) on the plasma MDA levels. * = Significantly different with respect to baseline value, P<0.05.
Fig. 4. Effect of treatment with topical melatonin (A), topical melatonin-sunscreen (group B), topical melatonin-oral melatonin (group C) and 4% hydroquinone (group D) on the plasma MDA levels.
- Data are expressed as mean ± SEM.
- Treatment with placebo starts after ending of 90 days of different treatment regimens.
- Baseline values in all treatment groups were significantly different from control.
- Non-identical superscripts (a, b, c) among different groups are consider significantly different, P<0.05.
- P<0.05 with respect to day 90.
Moreover, treatment with topical 4% hydroquinone cream (group D) showed not significant elevation in the level of GSH during 90 days of treatment (P>0.05) as presented Fig. 5. Again, stopping these four modes of treatment and continuing treatment with placebo for 30 days strongly abolished the previous effects elicited by these four regimens with the result of elevation in GSH levels, a value which not significantly different from the baseline levels (P>0.05) as shown in Fig. 5. When the effect of the four treatment regimens is compared at the end of day 90, significant difference in the level of GSH was reported only in group D (4.28%) which in comparison to that in group A (5.76%), group B (5.22%) and group C (5.38%) (P<0.05) as demonstrated in Fig. 6.