Melasma: A Clinical and Epidemiological Single-Group Observational Study in the Greek Population

Abstract

Introduction

Melasma is a common acquired disorder of melanogenesis that predominately affects women and presents as hyperpigmented skin lesions mainly located on the face. The study aims to investigate the epidemiologic characteristics and hormonal profiles in melasma patients.

Methods

One hundred fifty patients were enrolled in this study in a tertiary care hospital. Clinical patterns, pigment depth, disease severity, underlying conditions, and heredity were recorded. Endocrinologic profile and vitamin D levels were assessed.

Results

On clinical examination, the condition indicated a centrofacial localization in 74% of the patients. Extra facial melasma was noticed in 10 patients who had centrofacial melasma to begin with. Wood's lamp examination showed the dermal type as the most common. A family history of melasma was noted in 38% of the patients. Melasma Area and Severity Index (MASI) score ranged from 0.3 to 10.8, with a mean score of 4.12 ± 2.06. Pregnancy-induced melasma was reported in 36.1% of the patients. In 17.4% of women, melasma was related to using oral contraceptives. In 22% of patients, mild vitamin D deficiency was detected, while 21% had thyroid disorders.

Conclusion

There is a strong correlation between family history and prevalence of melasma. Sun exposure is a major precipitating factor and should be carefully addressed in Mediterranean countries like Greece. However, other factors such as concomitant medication, multiple pregnancies, use of oral contraceptives, thyroid disorders and vitamin D deficiency might precipitate melasma.

Key Summary Points

Why carry out this study?

Melasma is a pigmentation disorder that predominately affects women with dark phototypes worldwide.

It is usually localized in areas of high visibility like the face, resulting in depigmentation and high-cost treatments that are occasionally repeated every year.

This study investigated the potential role of risk or exacerbating factors in a Mediterranean population of melasma patients.

What was learned from the study?

There is a strong correlation between family history and prevalence of melasma. Sun exposure, multiple pregnancies, use of oral contraceptives, thyroid disorders and vitamin D deficiency might precipitate melasma.

In the melasma population studied, sun exposure was restrained as the patients did not report even a single sunburn, yet it was enough to develop facial and extra-facial melasma. Consequently, consultations should stress the need for broad-spectrum sunscreen for an indefinite period, especially in Mediterranean countries where patients experience daily sunshine almost all year round. Vitamin D supplements can be considered as adjuvant therapy. Thyroid tests might be considered when evaluating melasma.

Introduction

Melasma is a disorder of melanogenesis characterized by acquired hyperpigmentation of the skin. It occurs symmetrically on sun-exposed areas and mainly affects women of childbearing age [1]. Distribution of the lesions results in different phenotypes: centrofacial, which is the most common and involves the frontal, nasal, cheek, upper lip, and zygomatic area; malar, which involves the nasal and cheek area; and mandibular, which occurs in the jawline and chin [2]. Extra-facial melasma has been recently reported, affecting the neck, arms, and sternum [3].

Diagnosis of melasma is based on patient history and clinical appearance, and confirmation is assisted by Wood's light examination, which can also provide data on the depth of melanin deposition and predict treatment outcome [2]. Biopsy is rarely required to differentiate melasma from other types of hyperpigmentation. Dermoscopic features observed include a dark brown, well-defined network in the stratum corneum, with shades of light brown, an irregular network in the lower layers of the epidermis, and a blue-gray color in the dermis. Telangiectasia is present in many patients [4]. A recent study suggested a new diagnostic system for melasma using a large sample of melasma images to compare the diagnostic performance of multiple deep learning model [5]. Etiologic factors include genetic influences, ultraviolet radiation, pregnancy, hormonal therapies, cosmetics, and phototoxic drugs [6, 7]. As melasma predominately affects women, having skin lesions in visible areas is related to significantly higher anxiety, depression, and impaired health-related quality of life [8].

The present study aimed to investigate the clinical and epidemiologic characteristics and hormonal profile of melasma patients and explore whether vitamin D deficiency is correlated with the disease.

Methods

The local Ethics Committee approved this single-group observational study (registration no. 2959/11-6-18). The study complied with the principles laid down in the Declaration of Helsinki. Patients with melasma were eligible for inclusion if they were ≥ 18 and had Fitzpatrick skin types I–VI. Minors were excluded from participation as were patients with other hypermelanosis skin disorders and those last receiving therapy > 6 months before initiation of the study. Informed consent was obtained from all participants.

Demographics and a full medical history, including duration and natural history of the disease, underlying conditions, heredity, and the burden of melasma on quality of life, were recorded. Disease severity was assessed using the MASI score. Wood’s light was used to evaluate pigmentation depth.

Endocrinologic profile was assessed, including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone, testosterone, and prolactin. In addition, free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase (anti-TPO) were tested. Thyroid function was classified as normal when TSH and FT4 were within normal reference limits. A diagnosis of hypothyroidism or hyperthyroidism was made when TSH was elevated or decreased, respectively, or if the patient had a current diagnosis by an endocrinology specialist. Hypothyroidism and hyperthyroidism were considered subclinical diagnoses when FT4 levels were within the normal range or subclinical. The presence of anti-TPO antibodies was considered indicative of autoimmune thyroiditis.

For the determination of vitamin D, a blood sample was taken from the patients; after centrifugation, serum levels of calcidiol (25-hydroxy-vitamin D) were determined.

Statistics were measured and presented as mean ± standard deviation for quantitative variables and absolute and relative (%) frequencies for qualitative variables. The significance of differences was tested using an independent Student’s t-test or one-way ANOVA (for comparison of more than 2 variables) for quantitative variables and a chi-square test for qualitative variables.

Results

The study population comprised 150 patients diagnosed with melasma. All the participants were educated at least up to the high school level. The epidemiologic characteristics including gender, age, Fitzpatrick phototype and distribution of melasma based on clinical pattern and depth of the lesions are presented in Table 1.

Table 1.

Epidemiologic characteristics and distribution of melasma based on clinical pattern and depth of the lesion

Variables	Number of subjects	%
Gender
Male	6	4
Female	144	96
Age group (in years)
20–40	80	53.3
> 40	70	46.7
Skin phototype
Ι	1	0.7
ΙΙ	36	24
ΙΙΙ	78	52
ΙV	33	22
V	2	1.3
Pattern of melasma
Centrofacial	111	74
Malar	36	24
Mandibular	3	2
Type of melasma
Dermal	78	52
Epidermal	36	24
Mixed	33	22
Undetermined	3	2

Extrafacial melasma was noticed in 10 patients who had centrofacial melasma to begin with. Disease onset was frequently during reproductive ages as in 46% of cases onset was between 23 and 34 years, while the mean duration of the disease was 5.35 ± 4.45 years. MASI score ranged from 0.3 to 10.8, with a mean score of 4.12 ± 2.06. A higher MASI score was statistically significantly associated with longer disease duration (r = 0.24, p < 0.001), while no difference was found between skin phototypes (F = 2.62, p = 0.08).

The distribution of possible risk factors for melasma is described in Table 2. Pregnancy occurred in 132 (91.6%) of the women in our study and pregnancy-induced melasma in 52 (36.1%); 26.9% of these patients stated that their lesions started during the second pregnancy. An additional 17.4% of women indicated that their lesions were related to using oral contraceptives.

Table 2.

Distribution of possible risk factors for melasma

Variables	Number of subjects	%
Family history	57	38
Pregnancy	52	36.1
Oral contraceptives	25	17.4
Exposure to UV light
Work	45	30
Leisure activities	32	21.3
Solarium	52	34.7
Hormonal factors
Hypothyroidism	12	8
Hyperthyroidism	1	0.7
New finding—thyroid abnormalities	7	4.7
New finding—thyroiditis	11	7.3
LH, progesterone, estradiol	8	5.5

When facial skin care habits were examined, approximately 42% of women reported regular application of fragrance body products, 14% facial skin care with fragrance, 8% facial exfoliating products, and 20% essential oil-based products. Furthermore, 48% reported regular removal of unwanted hair from their face.

In 22% of patients, mild vitamin D deficiency was detected with serum values of 20–30 ng/ml. These patients had a mean MASI score of 7.06. Twelve patients (18%) had a known history of hypothyroidism, while one patient (1.5%) had hyperthyroidism. In 7 patients with no previous known history of thyroid disease (4.6%), laboratory testing revealed abnormal serum TSH levels, and 11 (7.3%) had high serum anti-TPO titers and were referred for endocrinologic evaluation. In contrast, the remaining patients had normal thyroid function.

Eight patients (5.3%) showed decreased LH, progesterone, and estradiol levels with no abnormalities in testosterone or prolactin levels. Endocrinologic evaluation in these cases reported mild ovarian dysfunction.

Discussion

Melasma is one of the most common skin disorders worldwide. Studies in Nepal, Saudi Arabia, and Brazil showed that melasma was one of the main reasons for providing dermatologic care [8]. According to a survey by the Brazilian Society of Dermatology in 2006, pigmentation disorders are the third most important group of skin diseases. Of these, 61.88% of cases were related to melasma [9]. Results remained similar in a survey 13 years later [10]. Melasma has been reported in all ethnic groups and populations; however, higher prevalence is observed in individuals with a higher amount of pigment in the skin, such as Southeast Asians, Middle Eastern Asians, Mediterranean Africans, Hispanics, and Brazilians [11–14].

Melasma results from a local change in pigmentation, and it occurs more frequently in individuals with intermediate Fitzpatrick phototypes III–V and rarely in extreme skin types [15–26]. In agreement with our data, many other studies show that the condition mainly affects women of reproductive age, while male patients account for a minority of cases.

Pigment depth is an important therapeutic consideration as dermal pigment may take longer to resolve. Targeting the inhibition of epidermal melanogenesis, which is the cause of dermal pigment, is always a treatment goal since new deposition will be inhibited and deposited pigment might slowly resolve. Data vary regarding the distinct patterns and depth of melanin. In the population studied, centrofacial was the predominant presentation (73%) followed by malar (24%) and maxillary (3%). Centrofacial type has been reported as the most common by many authors [8, 17, 18, 21–23] and malar in several other studies [15, 19, 20, 25]. Wood’s light determines the melasma depth, and its use requires minimal skill. Per our results, many studies have shown epidermal melasma as the most common one [16, 20]. Dermal melasma has also been reported as predominant in others [17, 23]. However, it has been suggested that dermal melanin deposition might be under-recognized by Wood's lamp. Additionally, it is not considered a suitable method for a group of patients with dark-skin type (V–VI) [16].

Extra facial melasma might be due to the progression of facial melasma to extra facial sites over time. The time interval between the appearance of melasma on the face and extra facial sites has been estimated to be up to 20 years in a study by Daroach et al. [3]. Therefore, photoprotection of body areas and the face should be advised in melasma patients.

According to our study, 38% of the patients had a family history of melasma in first- or second-degree relatives. Similar rates of positive family history were reported by many other published studies [2, 15, 21–24, 27, 28]. Family history was found to be one of the major aggravating factors in men by Sarkar et al. [20]. Tamega et al. highlighted positive family history in 56.3% of the patients [29]. Rates > 60% have also been reported [19, 31]. Individuals with intermediate phototypes and a family history of melasma have been suggested to be more prone to develop earlier onset of disorder [19].

MASI score is widely used to assess the severity of facial melasma. Scientific efforts to develop outcome sets for clinical trials seek to establish improved evaluation from the clinician and patient perspectives [32]. In our population, the mean MASI was 4.12 ± 2.06. Similar results were reported by Kunninpuram et al. [31], but higher scores have also been reported [33]. Recording an objective outcome, though time-consuming, is helpful to evaluate therapeutic response since even minor MASI reductions are considered encouraging for treatment continuation.

Hormones, in particular estrogen and progesterone, might play a role in melasma pathogenesis. Increased prevalence of melasma during pregnancy, or in association with oral contraceptive agents or menopausal hormone therapy uptake, has been well documented [2, 17, 19, 21, 23, 25, 27, 29–31, 33, 34]. Estimated melasma risk has been reported to be up eight times higher in women who use contraceptive pills [17]. In the study population, the majority (91.6%) of the women recorded pregnancy, and a smaller proportion reported that their lesions started during their second pregnancy. In addition, 17.4% of women reported that their lesions were related to oral contraceptive use. Estrogens have been proposed to have a more significant role than progesterone, probably stimulating melanogenesis through receptors on melanocytes [6]. Extra facial melasma on the forearms has been associated with the perimenopausal state and use of topical estrogen replacement therapy [35]. Further studies showed that extra facial melasma was more common in postmenopausal women than in those who did not experience menopause [19]. Our results showed abnormal LH, progesterone, and estradiol levels in a small percentage of melasma patients (5.3%). Women with melasma who have not conceived are shown to have estrogens within normal limits but elevated levels of estrogen receptors within the lesions. In contrast, high estrogen levels have been associated with both the onset and maintenance of the disease [7, 36]. Literature data on progesterone's role in postmenopausal women with melasma remain conflicting. Authors have reported that, in this population, prescribed progesterone increases the risk of developing melasma, while prescribed estrogen alone does not, giving progesterone a primary role in the development of the disease. [7].

Ultraviolet (UV) light induces reactive oxygen species and promotes melanin production in the skin [37]. In the population studied, patients reported sun exposure as a triggering or aggravating factor (intense sun exposure for their work needs or open-air activity). Still, many patients reported never suffering sunburn (42%), and almost half of our study patients reported regular sunscreen use. Solar exposure has been reported as both a triggering and an aggravating factor by many authors [17, 19–21, 23, 24, 29–32, 38, 39]. Increased time spent outdoors has also been shown to increase the risk of melasma onset during pregnancy [27]. In accordance with our findings, a significant correlation between the duration of sun exposure and disease severity has been published [22, 25]. Using a solarium has been reported by 34.7% of our patients, being implicated in melasma pathogenesis. A statistically significant higher risk of skin cancer with the use of sunbeds has been consistently demonstrated [40]. In many countries, not including Greece, they have been forbidden since the 2000s. Legislation restricting sunbed use is strongly suggested by the authors.

Most of our melasma patients used fragranced skin products as a daily routine. Ingredients in perfumed cosmetics might result in phototoxic reactions and the onset of melasma [38]. Melasma patients have previously shown positive patch test results for cosmetics [41]. Cosmetics may cause cytolysis and melanin incontinence at the basal layer following irritant reactions, resulting in low-grade inflammation and hyperpigmentation. If such an association is suspected, patch testing could be considered an additional diagnostic tool. In India, mustard oil, a well-known photosensitizer, is widely used on the face as an emollient and has been shown to act as a melasma trigger in predisposed individuals [42]. Systemic agents including anti-epileptic, antimalarial, antipsychotic, and cytotoxic/antineoplastic medications, have been reported to induce hyperpigmentation potentially [39].

Thyroid hormones have been associated with the pathogenesis of melasma, possibly through the induction of inflammatory cytokine production, which results in melanogenesis. Several studies have shown an increased incidence of thyroid disease in patients with melasma compared to healthy controls [2, 15, 25, 43–45]. Melasma patients have been found not only with thyroid hormone abnormalities but also with positive anti-TPO antibodies [43]. Even higher association rates are given by a more recent study approximating a positive history of hypothyroidism at 21% [46]. In our study, 21% of the patients had thyroid abnormalities (pre-existing and new findings). However, due to the absence of a control group, safe conclusions concerning the correlation between melasma and thyroid disease cannot be obtained.

Vitamin D has been demonstrated to stimulate melanogenesis and to regulate the activation, proliferation, and migration of melanocytes; therefore, it has been used to improve skin pigments [47]. Given the influence of vitamin D on the skin and the large prevalence of melasma in the public, their association will be examined further. Few published studies have shown that vitamin D levels in melasma patients are lower than in healthy controls [26, 48, 49]. A significant correlation was found between patients having melasma and low serum vitamin D levels with a p-value of 0.050 [49]. Patients in another melasma study had a significantly lower average serum calcidiol level than ethnicity- and sex-matched controls without melasma [26]. These agree with our results, as mild vitamin D deficiency was detected in 22% of our patients. These 30 patients had higher mean MASI scores than the mean MASI score of the total study population, suggesting a possible correlation between low vitamin D levels and melasma severity. Shope et al. even suggest that since patients with melasma have significantly lower serum vitamin D levels than their healthy counterparts, they may benefit from vitamin D supplementation [26].

Studies of melasma epidemiology, phenotypes, risk, triggering factors, and laboratory evaluation are important for developing severity tools, patient-oriented outcomes, and treatment guidelines. Triple combination topical treatment and sun protection are currently the gold standard in melasma therapeutics, but improvement is often temporary. Microneedling, peeling, laser, and light devices occasionally have been beneficial [50, 51]. Tranexamic acid (TXA) is believed to act in melasma by preventing the activation of melanocytes by UV light, hormones, and injured keratinocytes through the inhibition of the plasminogen activator system present in epidermal basal cells and keratinocytes [52]. Due to its mechanism of action, TXA, especially in its systemic administration, may improve clinical appearance and reduce the likelihood of recurrence. A better understanding of the disease is needed to develop targeted therapies for each pathogenetic pathway. Limitations of this study include the absence of a control group, inclusion and exclusion criteria, and identification of potential bias. Additionally only patients having phototypes II–IV presented and were included, reflecting characteristics of the local population. Concomitant medication, hormonal imbalances due to pregnancy, hormonal replacement therapy, hormonal contraceptives, thyroid disease, and vitamin D deficiency can be considered confounding factors.

Conclusion

The multifactorial etiology of melasma makes this skin condition difficult to treat and likely to recur. There is a strong correlation between family history and prevalence of melasma. Sun exposure is a major precipitating factor; however, other factors such as concomitant medication, multiple pregnancies, use of oral contraceptives, thyroid disorders, and vitamin D deficiency might precipitate melasma. Melasma patients should use broad-spectrum sunscreen for an indefinite period, especially in Mediterranean countries like Greece, where patients experience daily sunshine almost all year round. A sunburn is not described in most patients; it is just long-lasting daily sun exposure. Sun protection should be used on the body and face to prevent the development of extrafacial melasma. A greater understanding of its pathogenesis is needed as this will help develop a multimodal therapeutic approach for this common and challenging condition.

Author Contributions

Eftychia Platsidaki: concept and design, interpretation of data, drafting the manuscript, statistical analysis. Vasiliki Markantoni: acquisition of data. Alexandros Katoulis: concept and design. Electra Nicolaidou: concept and design. Dimitrios Rigopoulos: drafting the manuscript. Alexandros Stratigos: drafting the manuscript. Stamatios Gregoriou: concept and design, drafting the manuscript, revising it critically for important intellectual content.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Eftychia Platsidaki, Vasiliki Markantoni, Electra Nicolaidou, Alexander Katoulis, Dimitrios Rigopoulos, and Alexandros Stratigos have nothing to declare. Dr. Stamatios Gregoriou is an editorial board member. Dr. Stamatios Gregoriou was not involved in the section of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

The local Ethics Committee approved this single-group observational study (registration no. 2959/11-6-18). The study complied with the principles laid down in the Declaration of Helsinki. Informed consent was obtained from all participants.