Clinical and epidemiological characterization of patients with Melasma in outpatient consultation

López Henríquez Aldanarys; Ortega Dugrot Yanet; Valdivieso Romero Jacqueline Fidelina; Agüero de la Torre Katia; Mesa Cañizares Aymara; Ferrer González Yodeisy

doi:10.62486/pc2026148

Abstract

Melasma is a hyperpigmentation of multifactorial origin triggered by a combination of environmental, genetic, and hormonal factors, which are important components of quality of life. Objective: To clinically and epidemiologically characterize melasma in patients seen in an outpatient clinic. Methodological design: An observational, descriptive, retrospective, and cross-sectional study was conducted in the outpatient clinic of the “General Calixto García” University Hospital between January 2018 and December 2019. Results: In total, 43.6% of the participants were between 40 and 49 years old. A total of 89.7% were female. A total of 43.6% were classified as skin type III. Sun exposure was the triggering factor for 56.4% of the events. The duration of the condition was between 1 and 4 years in 38.5% of the patients. In 61.5% of the patients, the melasma was centrally distributed on the face. A total of 56.4% had epidermal melasma. A total of 61.5% had moderate-intensity melasma. A total of 33.3% had received prior topical treatment. Conclusions: Female patients aged 40–49 years with skin phototype III predominated. The main risk factor was sun exposure, and the duration of the condition was between 1 and 4 years in most patients. More than half of the patients presented with epidermal melasma of moderate severity distributed in the central facial region. The most frequently used previous treatment was topical therapy.

Keywords

melasma, chloasma, hydroquinone, chemical peel

INTRODUCTION

Human skin is inherently colorful. Even within the H. sapiens species, skin color spans an exquisite range, from the lightest ivory to the darkest brown. This diversity is due to the amount of pigments contained in the skin. The primary pigment is melanin, which occurs naturally and provides a dark color. In the human body, melanin is capable of absorbing, scattering, and reflecting light of different wavelengths, acting as a natural sunscreen.

Melasma is a chronic acquired hyperpigmentation of the skin. The word melasma derives from the Greek root melas, meaning black, and refers to the dark brown discoloration observed in this condition. The term “chloasma,” derived from the Latin chlóos and the Greek cloazein, meaning green, is also used in the medical literature, but it is semantically incorrect. It has also been referred to as the “pregnancy mask” and “patch,” among other terms. There are references to the condition dating back to the time of Hippocrates (470–360 BC), who described processes of hypermelanization following exposure to the sun, heat, cold, and postflammation.1 It is the third most frequently diagnosed pigmentary disorder, followed by postinflammatory hyperpigmentation and vitiligo.1

The exact prevalence is unknown in most countries. It accounts for between 0.25% and 4% of patients seen in Southeast Asia and is the most common pigmentary disorder among the populations of India and Pakistan.1 It affects all ethnic groups, but it is particularly prevalent among Hispanics and Asians, especially those living in areas with high-intensity ultraviolet radiation (UVR). It occurs in up to 10% of the population in Latin America, where communities comprise a heterogeneous mix of Caucasian, Asian, African, and indigenous populations, with a wide range of phototypes and skin colors. 2,3

It occurs predominantly in females, although it can also occur in men, although it is less common, accounting for 10 to 20% of cases. It occurs in all skin phototypes but most frequently affects Fitzpatrick phototypes III through VI and is most common between the third and fourth decades of life, with an average age of onset of 30 years and an average duration of eight years. 1During pregnancy, its prevalence increases by as much as 50–70%. 4

The exact etiology of melasma is unknown; in one-third of individuals, it is considered an acquired melanosis of idiopathic origin, confined to the face, with a chronic course. The incidence of certain factors is thought to be related to the onset of melasma, with the most important causes being genetic factors—it is estimated that 30% of affected individuals have a family history—as well as racial factors and ultraviolet radiation. Pigmentation typically occurs during pregnancy and is related to increased expression of melanocyte-stimulating hormone, the use of oral contraceptives, hormone therapy with estrogen and progesterone, and chronic sun exposure. During pregnancy, the clinical presentation develops during the second and third trimesters. The use of certain cosmetics, such as perfumed soaps, also appears to play a role.3

The lesions consist of asymptomatic macules of varying sizes, light brown or dark brown in color, with varying degrees of pigmentation, irregular borders, and sometimes well-defined edges.3 The objective of the study was to clinically and epidemiologically characterize melasma in patients seen in outpatient clinics.

METHODS

An observational, descriptive, retrospective, and cross-sectional study was conducted in patients diagnosed with melasma who were seen at the outpatient clinic of the “General Calixto García” University Hospital between January 2018 and December 2019.

The study population consisted of all patients seen in the outpatient clinic. The sample comprised 39 patients diagnosed with melasma using Wood’s light, who were seen at the aforementioned location and during the aforementioned period and who met the inclusion criteria.

Inclusion criteria:

Patients over 18 years of age

Patients of any sex

Exclusion criteria:

Patients with incomplete medical history data

Patients who do not agree to participate in the study

The source of information was the medical records of each patient included in the study. The data collection forms were included in a data collection spreadsheet in which all general information related to the study was recorded:

Data collection form for included patients. All the information was reviewed and classified such that it could be subsequently subjected to the various stages of statistical analysis.

Data processing and analysis techniques: Using the collected data, a database was created in Microsoft Office Excel (Windows 10 version), which was subsequently exported to SPSS version 25.0 for analysis.

Ethical considerations

The study was conducted in accordance with the provisions of the Declaration of Helsinki regarding research involving human subjects. To conduct this study, authorization was requested from the Archives and Statistics Department to access the medical records of the patients studied, with the responsibility and obligation not to disclose the collected information and to maintain it in strict confidence. This study was reviewed and approved by the Scientific Council and the Ethics Committee of the “General Calixto García” University Hospital. Given that this is a retrospective study that relies solely on medical records, the dissemination of the information generated in this study will occur only after all the parties involved in the study have given their consent. All of the parties may use such information for scientific dissemination, provided that all the parties have been consulted beforehand. Approval was obtained from the ethics committee and the scientific council of the primary implementing unit; all the data will remain confidential and will be handled solely by the authors.

RESULTS

The most common skin phototype was phototype III in 17 (43.6%) patients, followed by phototype IV in 12 (30.7%) patients and phototype V in 7 (17.9%) patients (Table 1).

Table 1. Distribution of patients by skin phototype

N	N	Frequency	%
N	N	39	100.0
Skin phototype	Skin type I	-	-
Skin phototype	Skin type II	3	7.7
Skin phototype	Skin type III	17	43.6
Skin phototype	Skin type IV	12	30.7
Skin phototype	Skin type V	7	17.9
Skin phototype	Skin type VI	-	-

Source: Data collection form.

The main triggers of the disease were sun exposure in 22 (56.4%) patients, followed by hormone therapy in 17 (43.6%), family history in 15 (38.5%), and previous pregnancy in 12 (30.8%) patients (Table 2).

Table 2. Disease triggers

		Frequency	%
[empty cell]	[empty cell]	[empty cell]	[empty cell]
Trigger *	Family history	15	38.5
Trigger *	Hormone therapy	17	43.6
Trigger *	Stress	5	12.8
Trigger *	Previous pregnancy	12	30.8
Trigger *	Menopause	5	12.8
Trigger *	Photo exhibition	22	56.4

Source: Data collection form. *Some patients had more than one risk factor.

The most common distribution pattern of melasma was the midface in 24 (61.5%) patients (Table 3).

Table 3. Distribution pattern of melasma

N	N	Frequency	%
N	N	39	100.0
Distribution pattern	Mid-facial	24	61.5
Distribution pattern	Malar	5	12.8
Distribution pattern	Mandibular	2	5.1
Distribution pattern	Mixed	8	20.5

Source: Data collection form.

Melasma was classified as epidermal in 56.4% (n=22) of the patients, mixed in 28.2% (n=11), and dermal or indeterminate in 7.7% (n=3) of the patients (Table 4).

Table 4. Clinical form of melasma

N	N	Frequency	%
N	N	39	100.0
Clinical form	Epidermal	22	56.4
Clinical form	Dermal	3	7.7
Clinical form	Mixed	11	28.2
Clinical form	Undetermined	3	7.7

Source: Data collection form.

As shown in Table 5, 13 (33.3%) patients received topical treatments, 9 (23.1%) received laser treatment, and 5 (12.8%) received systemic treatment, whereas 12 (30.8%) did not receive any treatment.

Table 5. Previous treatments

N	N	Frequency	%
N	N	39	100
Treatment used	Topical	13	33.3
Treatment used	Systemic	5	12.8
Treatment used	Laser	9	23.1
Treatment used	None	12	30.8

Source: Data collection form.

DISCUSSION

Melasma can develop in individuals of any skin phototype; however, as observed in this thesis, skin phototypes III and IV tend to be the most affected. 2 . This corresponds to the results reported by Rivera et al. 6, where the predominant skin phototype in cases with melasma was phototype III in 32 (40.0%), followed by phototype IV in 25 (32.5%), phototype V in 13 (16.3%), and phototype II in 9 (11.3%).

Similarly, Piteri Alcantara et al. (6) reported that among cases with melasma, phototype III was most common in 10 (45.4%), followed by phototype IV in 6 (27.3%) and phototype V in 6 (27.3%). Additionally, in a thesis by Palacios Rosales and Parra Nieto 6, among cases of melasma, phototype III was most common, with 164 (62.6%), followed by phototype IV with 78 (29.8%) and phototypes V-VI and II with 10 (3.8%) each. Similarly, among the patients with melasma studied by Cassiano et al. (7), skin phototype III was most prevalent at 12 (60.0%), followed by skin phototype IV at 6 (30.0%) and skin phototype II at 2 (10.0%). Similarly, Nguyen et al. (8) reported that the majority of patients with melasma had skin phototype III (10, or 43.5%), followed by phototype II (7, or 30.4%), phototype IV (5, or 21.7%), and phototype V (1, or 4.3%).

Like other Latin American countries, Cuba is a multiethnic nation in which people of Caucasian descent, people of African descent, and largely mixed-race populations coexist. As a result of this mixture, distinct skin tones are observed, ranging from skin type II to skin type VI. 2

The etiology of melasma is multifactorial, and its pathogenesis is complex; therefore, various factors, such as skin type, family history, ancestry, sun exposure, pregnancy, hormone therapy, and stress, can trigger this condition. 2

The most prevalent triggering factor in this series was sun exposure, which is consistent with the results of the study by Sharma et al. (2), in which sun exposure was the main factor exacerbating melasma in 16 (53.3%) men with this condition. Similarly, in a study conducted by Gallardo and Sernaqué (2), sun exposure was the main trigger of melasma in 44.0% (n=42) of cases. UVA and UVB rays are the primary factors involved in the development of hyperpigmentation. UV rays stimulate melanogenesis through direct effects on melanocytes—1,2-diacylglycerols, nitric oxide, and cyclic guanylate monophosphate—and through indirect effects on keratinocytes—fibroblast growth factor, nerve growth factor, nd endothelin-1, and propiomelanocortin-derived peptides such as melanocyte-stimulating hormone and nitric oxide. Melanocytes, fibroblasts, and keratinocytes interact, and the expression of certain paracrine factors derived from keratinocytes is elevated in affected skin compared with that in normally pigmented skin. 2,3

Treatment with hormone therapy was the second most common triggering factor in this study, which is consistent with the findings of other authors, such as Mahdalena et al., 2 Alenizi and Alenizi 2 and Rivera et al. (2), and is because estrogens affect melanogenesis by inducing the synthesis of melanogenic enzymes such as tyrosine, tyrosinase Trp-1, and Trp-2, which activate tyrosinase, thereby stimulating melanocytes. If the body’s levels of estrogen or progesterone increase, the acceleration of melanogenesis will be affected. 2,3

The genetic basis of melasma suggests that the occurrence of the condition in first-degree relatives ranges from 41–61%, including identical twin sisters, while the prevalence in adults in the general population is between 16–28%. Familial melasma is associated with a longer duration and a reduced likelihood of induction by contraceptive hormones. 2

As observed in this and other studies, melasma lesions are primarily located on the face and typically follow three distribution patterns, with the midface pattern being the most common 2, appearing in more than half of patients.

With respect to the distribution pattern of melasma, Sánchez Secías 2 reported that the midface pattern was the most common at 57.4% (n=35), followed by the malar pattern at 29.5% (n=18), the midface plus forearms at 6.6% (n=4), and the mandibular and midface plus neck at 3.3% (n=2) each. Similarly, in a thesis conducted by López Valdés 2, mid-face melasma predominated in 84.2% (n=112), followed by mandibular melasma in 8.3% (n=11) and malar melasma in 7.5% (n=10).

In a study by Farahat et al. (2), the type of melasma identified on the basis of depth was epidermal in 21 (70.0%) patients, followed by mixed in 6 (20%) and dermal in 3 (10%). Similarly, in the study conducted by Santana Chiriboga and Zamora Vargas 2, the types of melasma classified by depth were epidermal in 73 (68.8%) cases, followed by mixed in 28 (26.4%) and dermal in 5 (4.7%). 3

Currently, there are numerous medical-aesthetic procedures that can be used to treat various forms of pigmentation in dermatology, such as the use of various peels or lasers. 2 Equally important are topical depigmenting agents, which should be used prior to any procedure and should be continued as part of maintenance therapy. This approach yields good results when treating any type of dyschromia.

Most participants with melasma in this study reported having sought some form of treatment to address this condition, while only a small percentage stated that they had not used any topical treatment. These findings are consistent with those of other studies 2,3, which estimate that approximately 30% of respondents used topical combinations as treatments for melasma.

CONCLUSIONS

Female patients aged 40–49 years with a skin phototype III predominated. The main risk factor was sun exposure, and the duration of the condition ranged from 1 to 4 years in most patients. More than half of the patients () presented with midface melasma of the epidermal type and moderate severity. The most frequently used prior treatment was topical therapy.

References

1 Basukala M, Jha A, Shrestha R, Poudel S. Effect of melasma on quality of life in patient with melasma using DLQI (Dermatology Life Quality Index): A cross sectional study. JKISTMC [Internet]. 2022 [citado febrero 2023]; 4(2)8:6-10. Disponible en: http://www.journal.kistmcth.edu.np/index.php/JKISTMC/article/view/207&ved
2 Bravo E. Clinical-epidemiological characteristics of melasma in the Peruvian Andes. 24th World Congress of Dermatology. Milan, Italy. [Internet]. 2019 [citado diciembre 2020]. Disponible en: http://www.wcd2019milan-dl.org/abstract-book/documents/abstracts/33.pigmentation/clinical-epidemiological-characteristics-of-melasma-655.pdf&ved.
3 Cestari, Arellano-Mendoza I. Melasma in Latin America: options for therapy and treatment algorithm. J Eur Acad Dermatology Venereol 2009; 23(9):760–72.
4 Chatterjee M, Neema S. Dermoscopy of pigmentary disorders in brown skin. Dermatol Clin 2018; 36(4):473-85.
5 Doolan B, Gupta M. Melasma. Australian Journal of General Practice [Internet]. 2021 [citado diciembre 2021]; 50(12):880-5. doi: 10.31128/AJGP-05-021-6002..
6 Farahat AA, El-Garhy LH, El-Mahdy NA, Ali BM. Evaluation of the efficacy and safety of topical and oral glutathione in treatment of melasma. Med J
7 Nigh Cairo Univ [Internet]. 2018 [citado septiembre 2021]; 86(6):3083-92. Disponible en: http://www.medicaljournalofcairouniversity.net.
8 Gaur K, Tomar A, Purohit S, Sharma M. Effect of root heal therapy (RHT) on melasma : A quincy experiment. Int Multispecialty J Heal 2017; 3(10):350–5.
9 Grimes PE, Ijaz S, Nashawati R, Kwak D. New oral and topical approaches for the treatment of melasma. Int J Womens Dermatol [Internet]. 2019 [citado diciembre 2020]; 5(1):30-6. Disponible en: https://www.linkinghub.elsevier.com/retrieve/pii/S2352647518300431
10 Habif GD. Clinical Dermatology. Séptima edición. Mosby, Elsevier 2020.
11 Handel AC, Bartoli Miot LD, Amante Miot H. Melasma: a clinical and epidemiological review. Anais Brasileiros Dermatología 2014; 89(5):771-82.
12 Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol [Internet]. 2000 [citado diciembre 2020]; 39:57-106. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/10896812
13 Jablonski NG. The evolution of human skin and skin color. Annu Rev Anthropol [Internet]. 2004 [citado diciembre 2020]; 33(1):585-623. Disponible en: http://www.annualreviews.org/doi/10.1146/annurev.anthro.33.070203.143955..
14 Jusuf NK, Putra IB, Mahdalena M. Is there a correlation between severity of melasma and quality of life? Open Access Maced Med Sci [Internet]. 2019 [citado febrero 2023]. https://doi.org/10.3889/oamjms.2019.407..
15 Kagha K, Fabi S, Goldman MP. Melasma's impact on quality of life. J Drugs Dermatol [Internet]. 2020 [citado diciembre 2020]; 19(2):184-7. doi: 10.36849/JDD.2020.4663..
16 Kalayci MM. Pregnancy Mask: Melasma. Journal of Experimental and Basic Medical Sciences [Internet]. 2020 [citado diciembre 2020]; 1(2):65-7. doi: 10.5606/jebms.2020.75614..
17 Martínez Rico JC. Efectividad del ácido tranexámico oral vs formula triple combinada en el tratamiento de melasma moderado a severo: Estudio clínico controlado y aleatorizado. [tesis de Dermatología en línea]. Universidad Autónoma De Nuevo León. Nuevo León, México. 2019. [citado febrero 2022]. Disponible en: http://www.eprints.uanl.mx/20521/93/20521.pdf
18 Nunes Anacleto AC, Silva Fonseca A, Gonçalves AP, Pinheiro CM, Gomes Resende G, Pessoa Moreira L, et al. Melasma: revisão literária sobre tratamento e prevenção. Divinópolis. Minas Gerais, Brasil. [Internet]. 2021 [citado diciembre 2021]. Disponible en: http://www.crbm1.gov.br/site2019/wp-content/uploads/2022/04/ARTIGO-DE-REVISA%25CC%2583O-MELASMA.pdf&ved.
19 Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive review. Dermatol Ther (Heidelb) [Internet]. 2017 [citado diciembre 2020]; 7(3):305-18. doi:10.1007/s13555-017-0194-1..
20 Rao SK, Rajashekar TS, Ashraf A. Efficacy of intralesional tranexamic acid in melasma: assessment with Melasma Area Severity Index and Dermatology Quality of Life Index. Turkderm-Turk Arch Dermatol Venereol [Internet]. 2022 [citado febrero 2023]; 56:58-63. doi: 10.4274/turkderm.galenos.2022.42709..
21 Rose PT. Pigmentary disorders. Med Clin North Am 2009; 93(6).
22 Rzepka Z, Buszman E, Beberok A, Wrześniok D. From tyrosine to melanin: Signaling pathways3. and factors regulating melanogenesis. Postepy Hig Med Dosw [Internet]. 2016 [citado diciembre 2020]; 70(0):695–708. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/27356601.
23 Sánchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sánchez JL, Mihm MC Jr. Melasma: A clinical, light microscopic, ultraestructural and immunofluorescence study. J Am Acad Dermatol 1981; 4(6):698-710.
24 Sarkar R, Ghunawat S, Narang I, Verma S, Garg VK, Dua R. Role of broad‐spectrum sunscreen alone in the improvement of melasma area severity index (MASI) and Melasma Quality of Life Index in melasma. J Cosmet Dermatol [Internet]. 2019 [citado febrero 2023]; 18:1066-73. doi: 10.1111/jocd.12911..
25 Tamler C, Fonseca R, Pereira F, Barcauí C. Classificação do melasma pela dermatoscopia: estudo comparativo com lâmpada de Wood. [Internet]. 2022 [citado diciembre 2022]. Disponible en: https://www.pesquisa.bvsalud.org/portal/resource/pt/biblio-884356.

Declarations

Funding

The authors did not receive funding for the conduct of this research.

Conflict of interest

The authors declare that there are no conflicts of interest.

Authorship contributions

Conceptualization: Aldanarys López Henríquez

Data curation: Yanet Ortega Dugrot

Formal analysis: Katia Agüero de la Torre

Research: Aldanarys López Henríquez

Methodology: Jacqueline Fidelina Valdivieso Romero

Project management: Aldanarys López Henríquez

Supervision: Jacqueline Fidelina Valdivieso Romero

Visualization: Yanet Ortega Dugrot

Writing – original draft: Aldanarys López Henríquez

Writing–review and editing: Aldanarys López Henríquez, Yodeisy Ferrer González, Aymara Mesa Cañizares.

[ref1] 1 Basukala M, Jha A, Shrestha R, Poudel S. Effect of melasma on quality of life in patient with melasma using DLQI (Dermatology Life Quality Index): A cross sectional study. JKISTMC [Internet]. 2022 [citado febrero 2023]; 4(2)8:6-10. Disponible en: http://www.journal.kistmcth.edu.np/index.php/JKISTMC/article/view/207&ved

[ref2] 2 Bravo E. Clinical-epidemiological characteristics of melasma in the Peruvian Andes. 24th World Congress of Dermatology. Milan, Italy. [Internet]. 2019 [citado diciembre 2020]. Disponible en: http://www.wcd2019milan-dl.org/abstract-book/documents/abstracts/33.pigmentation/clinical-epidemiological-characteristics-of-melasma-655.pdf&ved.

[ref3] 3 Cestari, Arellano-Mendoza I. Melasma in Latin America: options for therapy and treatment algorithm. J Eur Acad Dermatology Venereol 2009; 23(9):760–72.

[ref4] 4 Chatterjee M, Neema S. Dermoscopy of pigmentary disorders in brown skin. Dermatol Clin 2018; 36(4):473-85.

[ref5] 5 Doolan B, Gupta M. Melasma. Australian Journal of General Practice [Internet]. 2021 [citado diciembre 2021]; 50(12):880-5. doi: 10.31128/AJGP-05-021-6002..

[ref6] 6 Farahat AA, El-Garhy LH, El-Mahdy NA, Ali BM. Evaluation of the efficacy and safety of topical and oral glutathione in treatment of melasma. Med J

[ref7] 7 Nigh Cairo Univ [Internet]. 2018 [citado septiembre 2021]; 86(6):3083-92. Disponible en: http://www.medicaljournalofcairouniversity.net.

[ref8] 8 Gaur K, Tomar A, Purohit S, Sharma M. Effect of root heal therapy (RHT) on melasma : A quincy experiment. Int Multispecialty J Heal 2017; 3(10):350–5.

[ref9] 9 Grimes PE, Ijaz S, Nashawati R, Kwak D. New oral and topical approaches for the treatment of melasma. Int J Womens Dermatol [Internet]. 2019 [citado diciembre 2020]; 5(1):30-6. Disponible en: https://www.linkinghub.elsevier.com/retrieve/pii/S2352647518300431

[ref10] 10 Habif GD. Clinical Dermatology. Séptima edición. Mosby, Elsevier 2020.

[ref11] 11 Handel AC, Bartoli Miot LD, Amante Miot H. Melasma: a clinical and epidemiological review. Anais Brasileiros Dermatología 2014; 89(5):771-82.

[ref12] 12 Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol [Internet]. 2000 [citado diciembre 2020]; 39:57-106. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/10896812

[ref13] 13 Jablonski NG. The evolution of human skin and skin color. Annu Rev Anthropol [Internet]. 2004 [citado diciembre 2020]; 33(1):585-623. Disponible en: http://www.annualreviews.org/doi/10.1146/annurev.anthro.33.070203.143955..

[ref14] 14 Jusuf NK, Putra IB, Mahdalena M. Is there a correlation between severity of melasma and quality of life? Open Access Maced Med Sci [Internet]. 2019 [citado febrero 2023]. https://doi.org/10.3889/oamjms.2019.407..

[ref15] 15 Kagha K, Fabi S, Goldman MP. Melasma's impact on quality of life. J Drugs Dermatol [Internet]. 2020 [citado diciembre 2020]; 19(2):184-7. doi: 10.36849/JDD.2020.4663..

[ref16] 16 Kalayci MM. Pregnancy Mask: Melasma. Journal of Experimental and Basic Medical Sciences [Internet]. 2020 [citado diciembre 2020]; 1(2):65-7. doi: 10.5606/jebms.2020.75614..

[ref17] 17 Martínez Rico JC. Efectividad del ácido tranexámico oral vs formula triple combinada en el tratamiento de melasma moderado a severo: Estudio clínico controlado y aleatorizado. [tesis de Dermatología en línea]. Universidad Autónoma De Nuevo León. Nuevo León, México. 2019. [citado febrero 2022]. Disponible en: http://www.eprints.uanl.mx/20521/93/20521.pdf

[ref18] 18 Nunes Anacleto AC, Silva Fonseca A, Gonçalves AP, Pinheiro CM, Gomes Resende G, Pessoa Moreira L, et al. Melasma: revisão literária sobre tratamento e prevenção. Divinópolis. Minas Gerais, Brasil. [Internet]. 2021 [citado diciembre 2021]. Disponible en: http://www.crbm1.gov.br/site2019/wp-content/uploads/2022/04/ARTIGO-DE-REVISA%25CC%2583O-MELASMA.pdf&ved.

[ref19] 19 Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive review. Dermatol Ther (Heidelb) [Internet]. 2017 [citado diciembre 2020]; 7(3):305-18. doi:10.1007/s13555-017-0194-1..

[ref20] 20 Rao SK, Rajashekar TS, Ashraf A. Efficacy of intralesional tranexamic acid in melasma: assessment with Melasma Area Severity Index and Dermatology Quality of Life Index. Turkderm-Turk Arch Dermatol Venereol [Internet]. 2022 [citado febrero 2023]; 56:58-63. doi: 10.4274/turkderm.galenos.2022.42709..

[ref21] 21 Rose PT. Pigmentary disorders. Med Clin North Am 2009; 93(6).

[ref22] 22 Rzepka Z, Buszman E, Beberok A, Wrześniok D. From tyrosine to melanin: Signaling pathways3. and factors regulating melanogenesis. Postepy Hig Med Dosw [Internet]. 2016 [citado diciembre 2020]; 70(0):695–708. Disponible en: http://www.ncbi.nlm.nih.gov/pubmed/27356601.

[ref23] 23 Sánchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sánchez JL, Mihm MC Jr. Melasma: A clinical, light microscopic, ultraestructural and immunofluorescence study. J Am Acad Dermatol 1981; 4(6):698-710.

[ref24] 24 Sarkar R, Ghunawat S, Narang I, Verma S, Garg VK, Dua R. Role of broad‐spectrum sunscreen alone in the improvement of melasma area severity index (MASI) and Melasma Quality of Life Index in melasma. J Cosmet Dermatol [Internet]. 2019 [citado febrero 2023]; 18:1066-73. doi: 10.1111/jocd.12911..

[ref25] 25 Tamler C, Fonseca R, Pereira F, Barcauí C. Classificação do melasma pela dermatoscopia: estudo comparativo com lâmpada de Wood. [Internet]. 2022 [citado diciembre 2022]. Disponible en: https://www.pesquisa.bvsalud.org/portal/resource/pt/biblio-884356.