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ORIGINAL ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 2  |  Page : 389-392

A study on the effect of estrogen, progesterone, and their cutaneous receptors in the pathogenesis of melisma


Department of Physiology, Faculty of Medicine, Menoufia University, Menufia, Egypt

Date of Submission11-May-2014
Date of Acceptance14-Sep-2014
Date of Web Publication18-Oct-2016

Correspondence Address:
Mai M Farag
Department of Dermatology, Faculty of Medicine, Mansoura University, Al Azher Street, Bani Ebaied-Mansoura Governorate, 35117
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.192411

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  Abstract 

Objective:
The aim of the study was to assess the efficacy of estrogen, progesterone, and their cutaneous receptors in the pathogenesis of melasma.
Materials and methods:
From January 2013 to June 2013, 40 female patients with melasma and 20 age-matched and sex-matched healthy individuals as the control group were included. Estrogen and progesterone were measured using IMMULITE 2000.
Results:
Concerning the serum estrogen and progesterone levels, the patients showed a statistically significant increase in progesterone levels with a mean value of 3.65 ± 13.11 when compared with the controls with a mean value of 3.63 ± 2.64.
Conclusion:
Increase in serum progesterone supports the role of pregnancy in melasma.

Keywords: estrogen, melasma, progesterone, progesterone hormones


How to cite this article:
Basha MA, Azmy RM, Farag MM. A study on the effect of estrogen, progesterone, and their cutaneous receptors in the pathogenesis of melisma. Menoufia Med J 2016;29:389-92

How to cite this URL:
Basha MA, Azmy RM, Farag MM. A study on the effect of estrogen, progesterone, and their cutaneous receptors in the pathogenesis of melisma. Menoufia Med J [serial online] 2016 [cited 2020 Apr 6];29:389-92. Available from: http://www.mmj.eg.net/text.asp?2016/29/2/389/192411


  Introduction Top


Melasma is an acquired hypermelanosis occurring symmetrically on sun-exposed areas of the body. Lesions are irregular light-to-dark brown macules and patches, usually involving the forehead, temples, upper lip, and cheek [1]. Melasma can affect any race; Asian and Hispanic female individuals are most commonly affected [2]. Women are affected in 90% of cases, as melasma is rare before puberty and most commonly occurs during their reproductive years [3]. Three patterns of melasma are recognized clinically: a centrofacial pattern, a malar pattern, and a mandibular pattern [4].

Natural and synthetic estrogen and progesterone have been incriminated for the pathogenesis of melasma because of its frequent association with pregnancy, use of contraceptive drugs, use of estrogens in postmenopausal women, and diethylbestrol treatment of prostate cancer [5].

Estrogen receptor (ER) and progesterone receptor (PR) belong to a superfamily of ligand-induced transactivators that exert their regulatory activity on discrete genes through DNA binding at individual hormone-responsive elements [6]. The molecular identification of ER and PR in the human melanocytes is of great importance to understand the mechanisms of induction of hyperpigmentation in melasma. The immunocytochemistry analysis demonstrated that ER and PR were expressed in the cytoplasms and nuclei of human melanocytes. Reverse transcriptase-PCR and sequence analysis confirmed the expression of ER and PR at the transcriptional level. Despite the presence of ER and PR, the physiological and pregnant levels of estrogen and progesterone showed inconsistent effects on the proliferation of tyrosinase activity of cultured human melanocytes [7].


  Materials and Methods Top


Inclusion criteria

  1. Female individuals with melasma.
  2. Patients aged above 30 years.


Exclusion criteria

  1. Pregnancy.
  2. Lactation.
  3. Oral contraceptive pills and other hormonal treatment.
  4. Polycystic ovarian syndrome and/or other endocrinopathies.


Methodology

Forty female patients with melasma and 20 age-matched and sex-matched healthy individuals as the control group were used in this study.

Each of the selected patient was subjected to the following: complete history taking and examination (general examination, dermatological examination).

Scoring of every case was carried out using melasma areas and severity index score (Kimbrough-Green et al., 1994). Area of involvement (A) includes analysis of four areas including the forehead (f) 30%, right malar region (rm) 30%, left malar region (lm) 30%, and the chin (c) 10%. The area of melasma involvement is given a numeric value from 0 to 6 (0 = no involvement, 1 = <10% involvement, 2 = 10–29% involvement, 3 = 30–49% involvement, 4 = 50–69% involvement, 5 = 70–89% involvement, and 6 = 90–100% involvement). Darkness (D) is estimated and given a value from 0 to 4 (0 = absent, 1 = slight, 2 = mild, 3 = marked, and 4 = maximum). Homogenecity (H) is estimated and given a value from 0 to 4 using the same scale as darkness. The melasma areas and severity index score is then calculated by the following formula:

0.3A(f)[D(f)+H(f)]+0.3A(rm)[D(rm)+H(rm)]+ 0.3A(lm)[D(lm)+H(lm)]+0.1A(c)[D(c)+H(c)]

Laboratory measurement (Siemens Healthcare, Erlangen, Germany) of estrogen and progesterone was performed using IMMULITE 2000, which is a solid-phase, two-site chemiluminescent immunometric assay. Sample collection by the use of an ultracentrifuge is recommended to clear lipemic samples. Hemolyzed samples may indicate mistreatment of a specimen before receipt by the laboratory; hence, the results should be interpreted with caution. Centrifuging serum samples before a complete clot forms may result in the presence of fibrin. To prevent erroneous results due to the presence of fibrin, ensure that complete clot formation has taken place before centrifugation of samples. Some samples particularly those from patients receiving anticoagulant therapy may require increased clotting time [8].

Statistical analysis

SPSS software was used to perform statistical analysis. (IBM Corporation, Armonk, New York, United States) Values for all continuous variables are quoted as mean, SD, and minimum and maximum throughout.

The t-test was used to assess the statistical significance of difference between two means. By knowing the (t) test and the degree of freedom, the P-value was calculated from special tables, and hence the significance of the results was determined from the 't' distribution tables.

P-value greater than 0.05 was considered insignificant difference, whereas P-value less than 0.05 was considered significant difference.

P-value less than 0.01 was considered highly significant difference, and P-value less than 0.001 was considered very highly significant difference.


  Results Top


Patients

There were 40 female patients having melasma and 20 female individuals as the control group. The age of selected patients with a mean value of 36.55 ± 5.77 and 34.30 ± 9.83 years of the control group showed nonstatistical significance.

[Table 1] shows that the serum estrogen levels in patients showed no statistical significance with a mean value of 98.51 ± 211.50 when compared with the controls with a mean value of 83.33 ± 58.70. However, patients showed a statistically significant increase in progesterone levels with a mean value of 3.65 ± 13.11 when compared with the controls with a mean value of 3.63 ± 2.64 (P = 0.03).
Table 1: Comparison between cases and the control group regarding serum estrogen and progesterone

Click here to view



  Discussion Top


The current study aimed to study the role of estrogen and progesterone in the pathogenesis of melasma through measuring their level in serum of studied melasma patients and through immunohistochemical localization of their receptors in tissues to throw spotlight on the pathogenesis of melasma.

In addition, there have been several reports demonstrating that estrogen treatment could lead keratinocytes to produce an increased amount of keratinocyte growth factor, and keratinocyte growth factor could increase pigment production and deposition in vitro and in vivo [9]. However, the results of studies on the effects of progesterone on skin pigmentation have been inconsistent. It has been reported that progesterone increased cell numbers and tyrosinase activity in melanocytes [0]. In contrast, significant inhibitory effects of progesterone on the proliferation of melanocytes in monoculture were also reported [1]. There has been no previous report on the expression of the ER and PR in melasma-affected skin except for one case report on ER expression in melasma-affected skin [2].

In the current study on melasma patients, no significant difference in serum estrogen level was shown, and there was elevation in serum progesterone level against normal control.

Serum estrogen did not differ in cases and control, which is against the results of several in-vitro studies suggesting that estrogen may be involved in the pathogenesis of melasma [3]. In contrast, Perez et al. [4] reported increased serum levels of leutinizing hormone alone and lower levels of serum estradiol in patients with melasma than in normal controls.

Serum progesterone was elevated in patients. This finding also agreed with the finding of Sato et al. [5] who reported that the main cause of melasma is considered to be an increase in progesterone (P4) in the serum during the luteal phase; however, it was in contrast with the study by Wiedemann et al. [1] who suggested that progesterone can inhibit proliferation of human melanocytes, which counteract the stimulator effects of estrogen. They showed that progesterone reduces the rate of proliferation of melanocytes in monoculture, whereas they had no significant effect on the tyrosinase activity.

In contrast, Jee et al. [6] reported that treatment with 17-estradiol for 10 days significantly showed increased neonatal melanocyte number and for 1 day exhibited decreased tyrosinase activity and melanin content. However, they suggested that the tyrosinase activity and melanin content were expressed as per cell. It is suggested that the proliferating activity stimulated by estradiol was greater than that by the tyrosinase activity and the melanin-producing activity. Maeda et al. [7] applied the adult melanocytes of Japanese male foreskin and showed that estradiol in the concentration range of 0.01–1.0 g/ml and 1 g/ml progesterone significantly increased the amount of TRP-1, and no significant effect on DOPA oxidase activity was detected after estradiol and progesterone treatment. In addition, estradiol and progesterone increase the area, the dendrites, and the perimeter per cell.

Kippenberger et al. [3] applied the reverse transcriptase-competitive multiplex PCR to normal human melanocytes and reported that 20 mol/l treatment with diethylstilbestrol and estradiol for 48 h led to about 1.5- to 2.5-fold increase in tyrosinase and TRP-2 transcripts. The authors reported for the first time that the sex steroids cause an increase in melanogenic enzyme transcripts in normal human melanocytes.

An increase in the tyrosinase activity could provoke the switch from pheomelanogenesis to eumelanogenesis. Activation of tyrosinase by estradiol might be an alternative to a direct receptor-mediated mechanism for the growth inhibitory effect observed in vivo and in vitro. The first is that certain prone melanocytes only can respond to estrogen and progesterone with a stimulation of growth. [8].

Progesterone effects on inflammatory cells were determined by administration of progesterone into the female reproductive tract, which resulted in increased numbers of Langerhans cells, a population of dendritic cells (DCs) found in the skin [9]. We have shown direct effects of progesterone on DC function, especially mature DCs. These results include inhibition of proinflammatory cytokine secretion, downregulation of DC-associated activation markers (MHC class II, CD80), and reduced T cell-proliferative capacity by these cells [0].


  Conclusion Top


The results of our study showed that melasma lesional skin contains more amount of melanin pigment.

The role of hormonal factor in the pathogenesis of the disease may be supported by the increase in serum progesterone, which supports the role of pregnancy in melasma.

In conclusion, this study suggests high evidence of efficacy of progesterone hormone in pathogenesis of melasma.

Conflicts of interest

There are no conflicts of interest.[20]

 
  References Top

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Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol 2005; 27:96–101.  Back to cited text no. 1
    
2.
Kang WH, Yoon KH, Lee ES, Kim J, Lee KB, Yim H, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol 2002; 146:228–237.  Back to cited text no. 2
    
3.
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4.
Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC Jr Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol 1981; 4:698–710.  Back to cited text no. 4
    
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Katsambas AD, Statigos AJ, Lotti TM. Melasma. In: Katsambas AD, Lotti TM, eds. European hand book of dermatology treatment. Berlin: Spring-Verlag; 2003;336–341.  Back to cited text no. 5
    
6.
Ranson M, Posen S, Mason RS. Human melanocytes as a target tissue for hormones: in vitro studies with 1 alpha-25, dihydroxyvitamin D3, alpha-melanocyte stimulating hormone, and beta-estradiol. J Invest Dermatol 1988; 91:593–598.  Back to cited text no. 6
    
7.
Im S, Lee ES, Kim W, Song J, Kim J, Lee M, Kang WH Expression of progesterone receptor in human keratinocytes. J Korean Med Sci 2000; 15:647–654.  Back to cited text no. 7
    
8.
Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, Romankiewicz JA, Heel RC Metoclopramide: an updated review of its pharmacological properties and clinical use. Drugs 1983; 25:451–494.  Back to cited text no. 8
    
9.
Pedchenko VK, Imagawa W. Estrogen treatment in vivo increases keratinocyte growth factor expression in the mammary gland. J Endocrinol 2000; 165:39–49.  Back to cited text no. 9
    
10.
Im S, Kim J, On WY, Kang WH Increased expression of alpha-melanocyte-stimulating hormone in the lesional skin of melasma. Br J Dermatol 2002; 146:165–167.  Back to cited text no. 10
    
11.
Wiedemann C, NägeleU, Schramm G, Berking C Inhibitory effects of progestogens on the estrogen stimulation of melanocytes in vitro. Contraception 2009; 80:292–298.  Back to cited text no. 11
    
12.
Lieberman R, Moy L. Estrogen receptor expression in melasma: results from facial skin of affected patients. J Drugs Dermatol 2008; 7:463–465.  Back to cited text no. 12
    
13.
Kippenberger S, Loitsch S, Solano F, Bernd A, Kaufmann R Quantification of tyrosinase, TRP-1, and Trp-2 transcripts in human melanocytes by reverse transcriptase-competitive multiplex PCR — regulation by steroid hormones. J Invest Dermatol 1998; 110:364–367.  Back to cited text no. 13
    
14.
PérezM, SánchezJL, AguilóF. Endocrinologic profile of patients with idiopathic melasma. J Invest Dermatol 1983; 81:543–545.  Back to cited text no. 14
    
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Sato M, Tsubota T, Yamamoto K, et al. Serum progesterone and estradiol-17beta concentrations in captive and free-ranging adult female japanese black bears [Ursus thibetanus japonicas]. J Vet Med Sci 2000; 4:116–122.  Back to cited text no. 15
    
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Jee SH, Lee SY, Chiu HC, Chang CC, Chen TJ Effects of estrogen and estrogen receptor in normal human melanocytes. Biochem Biophys Res Commun 1994; 199:1407–1412.  Back to cited text no. 16
    
17.
Maeda K, Naganuma M, Fukuda M, Matsunaga J, Tomita Y Effect of pituitary and ovarian hormones on human melanocytes in vitro. Pigment Cell Res 1996; 9:204–212.  Back to cited text no. 17
    
18.
Im S, Lee ES, Kim W, On W, Kim J, Lee M, Kang WH Donor specific response of estrogen and progesterone on cultured human melanocytes. J Korean Med Sci 2002; 17:58–64.  Back to cited text no. 18
    
19.
Wieser F, Hosmann J, Tschugguel W, Czerwenka K, Sedivy R, Huber JC Progesterone increases the number of Langerhans cells in human vaginal epithelium. Fertil Steril 2001; 75:1234–1235.  Back to cited text no. 19
    
20.
Butts CL, Shukair SA, Duncan KM, et al. Progesterone inhibits matures rat dendritic cells in a receptor mediated fashion. Int Immunol 2007; 19:287–296.  Back to cited text no. 20
    



 
 
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