Risk Factors for Facial Melasma in Women
This study demonstrated multiple factors independently associated with facial melasma in women, such as phenotype, family ascendency, sun exposure, medication, hormones and anxiety traits, and measured their risk association with the disease. Our patients with melasma presented similar phenotypes and clinical and demographic characteristics to Brazilian patients in a previous study.
Melasma incidence varied according to solar radiation and population ethnic composition, being more common in tropical regions and in patients with more melanized phenotypes. Hispanic, Asiatic (China, Korea, Japan, India, Pakistan), Mediterranean African and Middle Eastern populations are more affected than those with whiter skin. In Southeast Asia the prevalence reaches 40% in adult women and 20% in adult men. On the south coast of India, it affects 41% of rice workers.
Our study was performed in a tropical area (latitude 22°53'S) with a high annual ultraviolet (UV) index, and an estimated prevalence of melasma in adult women of 34% (A.C. Handel, P.B. Lima, V.M. Tonoli, L.D.B. Miot, H.A. Miot, unpublished data). It showed that higher phototypes (III–V), but not the extreme levels, were associated with melasma development, suggesting that epidermal melanin unit hyperactivity develops more easily in individuals who are more reactive to UV radiation. Two studies in Brazil with more than 1000 women, one in Tunisia with 197 cases, and another in nine countries with 324 patients also identified phototypes III–V in > 80% of cases.
The genetic component has a strong influence in melasma. Our sample showed a high frequency of affected families, with indigenous ancestry more commonly reported in cases. Inherent pigmentation and phototypes have a polygenic heritage. Similarly, in epidemiological studies, occurrence in immediate family is reported by > 40% of patients, as well as a high prevalence of Native American descent. Brazil, especially in the studied region, presents a higher admixture rate, especially indigenous, European and African. The melanogenic route is regulated by different genes, and various single nucleotide polymorphisms (SNPs) have been identified with different patterns in different populations. Two specific genes, EGFR and OPMR1, have shown SNPs that are associated with Native American ancestry, suggesting that Europeans and Americans regulate their pigmentation routes in a different way. In fact, melasma is less common in Europeans, and more common in Asians and Latin Americans, who have a common phylogenetic origin from human migrations from Africa. Hypothetically, melasma may be the result of postsomatic mosaicism, locally expressed indigenous or Asiatic genes. Verbal reporting of ancestry by subjects is predisposed to recall bias in both cases and controls, resulting in lower information precision. These results must be confirmed from genetic ancestry studies.
The risk of developing melasma increases with exposure to UV radiation. Pregnant mothers who perform activities in the sun have a higher chance (27%) of developing melasma during pregnancy. Our study revealed a higher proportion of individuals with melasma who had lived in rural or seaside settings, and who reported higher work or leisure sun exposure, but who had not reported sunburn, showing that chronic exposure is more important in developing the disease. Sunburn incidents are less common in higher phototypes. In fact our results pointed towards protection. A lack of association with sunburn was also identified in a study in Tunisia. There is also an association between dermatoheliosis and melasma severity, indirectly reinforcing the hypothesis of cumulative sun exposure.
Pregnancy and COC use are classically established risk factors in the literature. In a group of 250 Indian women, melasma was trigged by pregnancy in 22%, and pigmentation exacerbated in 14%. Other studies have reported that between 5% and 50% of patients identified pregnancy as a triggering factor. Melanogenesis can be stimulated by the hormone changes in pregnancy, with increased melanocortins (MSH), and oestrogen and progesterone levels; however, pregnancy-induced melasma is not associated with hyperpigmentation of other body areas. Similarly, studies have reported disease development after COC use in 8–34% of users, and a worsening picture in 38%. Oestrogen can induce pigmentation from nuclear receptor action and in a nongenomic form increasing tyrosinase expression.
Menstrual cycle changes can also lead to hormonal imbalance, such as polycystic ovary syndrome and insulin resistance, influencing melasma genesis, maintenance and worsening, as shown in Middle Eastern studies. Patients with melasma in our study presented a higher proportion of menstrual irregularities, bordering on significant when BMI was higher.
Melasma has an important visual impact causing psychosocial stress and prejudicing quality of life in sufferers. On the other hand, stressful events have been reported as disease triggers in 4–7%, and aggravating factors in 26·3% of cases in Brazil. In 1991, two stress-triggered cases of melasma were reported (death of relatives).
The hypothalamus produces releasing hormones for melanocortins (ACTH and MSH), which have a direct effect on pigmentation. Participation of the hypothalamus in the limbic system substantiates the hypothesis that emotions and stress reactions can induce a pigmentation response in susceptible individuals. There is also evidence that melanocytes have an individualized response to stress hormones, with the same hypothalamic–pituitary axis hierarchy. Epidermal melanin unit reaction to stress response hormone stimulation has not been studied in melasma, despite evidence of increased epidermal α-MSH secretion in damaged compared with adjacent normal epithelium.
Our study showed that patients with melasma presented a higher anxiety trait score as well as increased use of antidepressants and anxiolytics compared with the controls. Stress and depression are associated with higher cortisol levels and melanocortin production, which exert melanogenic activity. As the IDATE-T evaluates anxiety trait and not anxious state, we can affirm that patients in this sample who reacted in a more anxious way to everyday challenges, developed more melasma than the controls. Higher psychiatric medication use could be further proof of this risk profile.
Evaluating the interaction between IDATE-T score and length of time of COC use, we observed that in cases only, there was no concurrent linearity of association for individual risk variables, suggesting that they act in an independent manner in melasma development.
The same is suggested by the interaction between antidepressants and menstrual irregularity, where we see a higher frequency of antidepressant use in patients without menstrual cycle changes.
The limitations in this study include a lack of information on participant schooling and social level; however, there are no observations in the literature that associate these variables with melasma. Case–control studies are subject to memory and information bias. In our study, this could have occurred with family history, ascendency, comorbidities, medication use, alcohol and tobacco, weight and height, use of sunblock, and work and leisure sun exposure. Except for family history of melasma, we hope that there was similar imprecision of information between cases and controls, which should not greatly influence our final results. Generalization of results from this study is prejudiced by the fact that cases and controls were derived from a public service situated inland; however, group geographical homogeneity and patient social origin guarantee comparability between them.
Future prospective studies should elucidate the natural history of patients with melasma, analyse subgroups (e.g. clinical forms), and include an inheritance profile, based on incidence in patient offspring and differential expression of genes linked to pigmentation and ancestry in damaged and adjacent skin. Moreover, the results related to Amerindian ancestry should also be assessed in other countries with a lower ethnical admixture rate than the Brazilian population.
The investigation of risk factors for melasma allows statistical risk models to be built for identifying individuals susceptible to developing the disease, and the planning of primary prevention strategies in these groups, such as strong photoprotection measures, less exposure to sex hormones and earlier treatments.
Discussion
This study demonstrated multiple factors independently associated with facial melasma in women, such as phenotype, family ascendency, sun exposure, medication, hormones and anxiety traits, and measured their risk association with the disease. Our patients with melasma presented similar phenotypes and clinical and demographic characteristics to Brazilian patients in a previous study.
Melasma incidence varied according to solar radiation and population ethnic composition, being more common in tropical regions and in patients with more melanized phenotypes. Hispanic, Asiatic (China, Korea, Japan, India, Pakistan), Mediterranean African and Middle Eastern populations are more affected than those with whiter skin. In Southeast Asia the prevalence reaches 40% in adult women and 20% in adult men. On the south coast of India, it affects 41% of rice workers.
Our study was performed in a tropical area (latitude 22°53'S) with a high annual ultraviolet (UV) index, and an estimated prevalence of melasma in adult women of 34% (A.C. Handel, P.B. Lima, V.M. Tonoli, L.D.B. Miot, H.A. Miot, unpublished data). It showed that higher phototypes (III–V), but not the extreme levels, were associated with melasma development, suggesting that epidermal melanin unit hyperactivity develops more easily in individuals who are more reactive to UV radiation. Two studies in Brazil with more than 1000 women, one in Tunisia with 197 cases, and another in nine countries with 324 patients also identified phototypes III–V in > 80% of cases.
The genetic component has a strong influence in melasma. Our sample showed a high frequency of affected families, with indigenous ancestry more commonly reported in cases. Inherent pigmentation and phototypes have a polygenic heritage. Similarly, in epidemiological studies, occurrence in immediate family is reported by > 40% of patients, as well as a high prevalence of Native American descent. Brazil, especially in the studied region, presents a higher admixture rate, especially indigenous, European and African. The melanogenic route is regulated by different genes, and various single nucleotide polymorphisms (SNPs) have been identified with different patterns in different populations. Two specific genes, EGFR and OPMR1, have shown SNPs that are associated with Native American ancestry, suggesting that Europeans and Americans regulate their pigmentation routes in a different way. In fact, melasma is less common in Europeans, and more common in Asians and Latin Americans, who have a common phylogenetic origin from human migrations from Africa. Hypothetically, melasma may be the result of postsomatic mosaicism, locally expressed indigenous or Asiatic genes. Verbal reporting of ancestry by subjects is predisposed to recall bias in both cases and controls, resulting in lower information precision. These results must be confirmed from genetic ancestry studies.
The risk of developing melasma increases with exposure to UV radiation. Pregnant mothers who perform activities in the sun have a higher chance (27%) of developing melasma during pregnancy. Our study revealed a higher proportion of individuals with melasma who had lived in rural or seaside settings, and who reported higher work or leisure sun exposure, but who had not reported sunburn, showing that chronic exposure is more important in developing the disease. Sunburn incidents are less common in higher phototypes. In fact our results pointed towards protection. A lack of association with sunburn was also identified in a study in Tunisia. There is also an association between dermatoheliosis and melasma severity, indirectly reinforcing the hypothesis of cumulative sun exposure.
Pregnancy and COC use are classically established risk factors in the literature. In a group of 250 Indian women, melasma was trigged by pregnancy in 22%, and pigmentation exacerbated in 14%. Other studies have reported that between 5% and 50% of patients identified pregnancy as a triggering factor. Melanogenesis can be stimulated by the hormone changes in pregnancy, with increased melanocortins (MSH), and oestrogen and progesterone levels; however, pregnancy-induced melasma is not associated with hyperpigmentation of other body areas. Similarly, studies have reported disease development after COC use in 8–34% of users, and a worsening picture in 38%. Oestrogen can induce pigmentation from nuclear receptor action and in a nongenomic form increasing tyrosinase expression.
Menstrual cycle changes can also lead to hormonal imbalance, such as polycystic ovary syndrome and insulin resistance, influencing melasma genesis, maintenance and worsening, as shown in Middle Eastern studies. Patients with melasma in our study presented a higher proportion of menstrual irregularities, bordering on significant when BMI was higher.
Melasma has an important visual impact causing psychosocial stress and prejudicing quality of life in sufferers. On the other hand, stressful events have been reported as disease triggers in 4–7%, and aggravating factors in 26·3% of cases in Brazil. In 1991, two stress-triggered cases of melasma were reported (death of relatives).
The hypothalamus produces releasing hormones for melanocortins (ACTH and MSH), which have a direct effect on pigmentation. Participation of the hypothalamus in the limbic system substantiates the hypothesis that emotions and stress reactions can induce a pigmentation response in susceptible individuals. There is also evidence that melanocytes have an individualized response to stress hormones, with the same hypothalamic–pituitary axis hierarchy. Epidermal melanin unit reaction to stress response hormone stimulation has not been studied in melasma, despite evidence of increased epidermal α-MSH secretion in damaged compared with adjacent normal epithelium.
Our study showed that patients with melasma presented a higher anxiety trait score as well as increased use of antidepressants and anxiolytics compared with the controls. Stress and depression are associated with higher cortisol levels and melanocortin production, which exert melanogenic activity. As the IDATE-T evaluates anxiety trait and not anxious state, we can affirm that patients in this sample who reacted in a more anxious way to everyday challenges, developed more melasma than the controls. Higher psychiatric medication use could be further proof of this risk profile.
Evaluating the interaction between IDATE-T score and length of time of COC use, we observed that in cases only, there was no concurrent linearity of association for individual risk variables, suggesting that they act in an independent manner in melasma development.
The same is suggested by the interaction between antidepressants and menstrual irregularity, where we see a higher frequency of antidepressant use in patients without menstrual cycle changes.
The limitations in this study include a lack of information on participant schooling and social level; however, there are no observations in the literature that associate these variables with melasma. Case–control studies are subject to memory and information bias. In our study, this could have occurred with family history, ascendency, comorbidities, medication use, alcohol and tobacco, weight and height, use of sunblock, and work and leisure sun exposure. Except for family history of melasma, we hope that there was similar imprecision of information between cases and controls, which should not greatly influence our final results. Generalization of results from this study is prejudiced by the fact that cases and controls were derived from a public service situated inland; however, group geographical homogeneity and patient social origin guarantee comparability between them.
Future prospective studies should elucidate the natural history of patients with melasma, analyse subgroups (e.g. clinical forms), and include an inheritance profile, based on incidence in patient offspring and differential expression of genes linked to pigmentation and ancestry in damaged and adjacent skin. Moreover, the results related to Amerindian ancestry should also be assessed in other countries with a lower ethnical admixture rate than the Brazilian population.
The investigation of risk factors for melasma allows statistical risk models to be built for identifying individuals susceptible to developing the disease, and the planning of primary prevention strategies in these groups, such as strong photoprotection measures, less exposure to sex hormones and earlier treatments.
SHARE
