Comparation of Estradiol and Estriol Serum Levels in Different

Degrees of Melasma Severity in Pregnant Women

Tantari Sugiman, Dyah Ayu Savitri and Arif Widiatmoko

Department of Dermatology and Venereology, Faculty of Medicine, Universitas Brawijaya / dr. Saiful Anwar Regional

General Hospital, Malang, Indonesia

Keywords: Estradiol, Estriol, Melasma, Severity, Pregnancy.

Abstract: Estrogen, estradiol and estriol, is known to be capable of inducing melanogenesis and have been held

responsible for the pigmentation seen in pregnancy. This study was conducted to analyse serum levels of

estradiol and estriol in different degree of melasma severity in pregnant women. A cross-sectional study using

continuous sampling in pregnant women with melasma conducted in June - July 2017 at Dr Saiful Anwar

Regional General Hospital Malang, Indonesia. Inclusion criteria include pregnant women with melasma (15-

49 years). Pregnant women with previous history of non-pregnancy melasma, who are taking hormonal

contraceptives or taking hormonal drugs containing estrogen and taking phototoxic drugs excluded from the

study. History, physical examination, Wood Lamp, and measurement severity melasma using MSS (Melasma

Severity Score) was performed. Blood samples were drawn for serum estradiol and estriol serum examination

using ELISA method. Result from 25 pregnant women with melasma divided into four groups, clear (6

subjects), mild (5 subjects), moderate (9 subjects) and severe (5 subjects). Estradiol serum levels mean were

417.80 (clear), 836.60 (mild), 793.58 (moderate) and 891.00 (severe). Estriol serum levels mean obtained on

clear (94.67), mild (149.88), moderate (199.64) and severe (141.17). Significant different serum levels of

estradiol found in each group of MSS (p=0.015) and serum levels estriol did not significantly differ in each

group of MSS (p=0.454). This study concluded that estradiol serum levels in pregnant women with melasma

were different in melasma severity degrees, but estriol serum levels were not different in melasma severity

degrees.

1 INTRODUCTION

Melasma is also known by the name of chloasma or

mask of pregnancy (Newcomer et al, 1961) as it may

appear during pregnancy and is characterised by

symmetric hyperpigmentation lesions (Grawkrodjer

et al 2002) (Hindrtiatini, 2015). The incidence of

melasma is estimated to be about 0.2-4% of total

patients with skin disease in Indonesia (Praskoeswa,

2002).

Data obtained at dr Saiful Anwar Regional

General Hospital Malang, in 2014 melasma reached

338 (3.4%) patients from total of 9736 patients per

year, as the seventh of ten most common diseases in

the Dermatology and Venereology Outpatient. In

2015, the incidence of melasma decreased to 226

(2.7%) incidence of total 8310 patients per year. The

latest data obtained from Saiful Anwar's Dermatology

and Venereology Outpatients in 2016, the total

number patients of melasma as many as 185 (2.3%)

of total 7945 patients per year.

The predominance of melasma in women supports

the role of female sex hormones in one of the

pathogenesis of melasma, but the mechanism is

unclear (Handel et al, 2014). Estrogen enhancement

that increases α-MSH (Melanocyte-Stimulating

Hormone) expression in keratinocytes is thought to be

an essential key to explain the process of

hyperpigmentation occurring in the skin with

melasma (Im S et al, 2002). Estrogen is a steroid

hormone formed primarily of androstenedione. There

are three types of estrogens namely estrone, estradiol

and estriol.The potential of estradiol is 12 times the

estrone potential and eight times estriol, so estradiol

is considered the primary estrogen (Speroff et al,

2005). A study conducted by Gopichandani et al.

(2015) supports that the pathogenesis of melasma is

primarily affected by estradiol, evidenced by the high

levels of these hormones in melasma in pregnancy

was found to be lower than controls. Other estrogens

such as estriol and estrone are said to affect the

Sugiman, T., Savitri, D. and Widiatmoko, A.

Comparation of Estradiol and Estriol Serum Levels in Different Degrees of Melasma Severity in Pregnant Women.

DOI: 10.5220/0008151600950099

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 95-99

ISBN: 978-989-758-494-7

cytoplasm and estrogen core receptors that are known

expressed in melanocytes (Gopichandani et al, 2015).

In pregnancy especially in the third trimester, high

levels of estriol and estradiol are associated with high

levels of α-MSH which can increase tyrosinase and

dopachrome tautomerase production so that

melanogenesis increased and vulnerable to melasma

(Ortonne et al, 2009).

Melasma Area Severity Index (MASI) is used to

measure the clinical severity quantity of melasma

(Kimbrough et al, 1994). In addition to the MASI

scheme, a global degree of severity is also required to

estimate treatment success in melasma clinical trials.

Melasma Severity Score (MSS), used as a worldwide

degree, is commonly used in clinical trials research

and is expected to be clinically meaningful in

describing the severity of disease that is easy to use in

clinicians and patients (Rodrigues et al, 2016).

Miranti et al. (2016) reported that serum estradiol

levels were slightly higher in pregnant women with

melasma than pregnant women without melasma, but

this increase in numbers was not significant. That is,

serum estradiol levels are associated with the age of

pregnant women and gestational age, but not related

to MASI score or melasma types. Meanwhile, no

literature has examined serum estriol, which

produced only during pregnancy against the severity

of melasma. The study objective is to compare serum

estradiol and estriol levels in degrees of melasma

severity in pregnant women.

2 METHOD

This study used cross-sectional observational analysis

in Pregnancy Outpatient Clinic, Dermatology and

Venereology Outpatients Clinic in dr Saiful Anwar

Regional General Hospital Malang and Physiology

Laboratory Faculty of Medicine Universitas

Brawijaya Malang, East Java, Indonesia. After

Hospital Ethics Committee approvement, this study

carried out from June to July 2017. Calculation

sample was using single population proportion at a

precision of 5%, 95% confidence interval and

prevalence of melasma in pregnancy 43,5%

(r=0,435).

This study population was 25 pregnant

women with melasma visited Outpatient Clinic.

Samples in this research are all population that fulfil

the criteria of inclusion and exclusion. Inclusion

criteria including pregnant women with melasma

aged 15-49 years, pregnant women with melasma that

appear during pregnancy either primigravida or

multigravida and willing to be the subject of research

and signed informed consent. Exclusion criteria for

pregnant women with prior history of melasma that

appear not during pregnancy, pregnant women using

hormonal contraceptives and hormone replacement

therapy (estrogen, progesterone or both), pregnant

women taking phototoxic drug (antibiotics, NSAIDs,

diuretics, retinoids, epidermal growth factor

inhibitors, anti-fungal, tranexamic acid,

antihistamines and neuroleptics), and Gemelli

pregnancy.

The diagnosis of melasma and determination of

severity made by anamnesis, physical examination

with a typical clinical picture then calculated

Melasma Severity Score by converting MASI score

into MSS. Melasma Severity Score divided into clear

(0-6.9), mild (> 6.9), moderate (>12,4) and severe

(>20,2).

Measurements made by three consecutive

examiners on the same day. Collect 5cc of blood

samples in a tube of SST (Serum Separator Tubes)

then centrifuge for 10 minutes at 2000-3000 rpm

within 20 minutes. After all samples collected, serum

estradiol and estriol levels evaluated by ELISA

method. After filling the data on the data collection

sheets, then the data is processed using the Statistical

Package for Social Sciences (SPSS) version 18. Test

the normality of population data comparability using

Kolmogorov-Smirnov test. The difference analysis

serum estradiol and estriol level in each group of MSS

using One-Way ANOVA.

3 RESULT

In this study, the samples obtained as many as 25

pregnant women with melasma with the age range 15-

49 years. The mean age of the study subjects was

32.50 with a standard deviation of 7.77. The age of

majority of subjects with melasma is 31-40 years.

Age of pregnancy obtained in the third trimester of 21

people (84%) followed by the second trimester as

much as three people (12%) and one person (4%) first

trimester of the 25 subjects, the duration of exposure

to sunlight less than 6 hours as many as seven people

(28%) and as many as 18 people (72%) experienced a

duration of exposure to sunlight more than 6 hours a

day. Followed by sun exposure time at 09.00 to 15.00

as many as 18 people (72%) and sunlight exposure

time is less than 09.00 as many as seven people

(28%).

RCD 2018 - The 23rd Regional Conference of Dermatology 2018

Table 1: Baseline Characteristics.

Group

Amount

(n=25)

Percentage

(n=100%)

Age

15-20

21-30

31-40

41-49

24%

52%

16%

0.489

Gestational age

(Trimester)

III

12%

84%

0.206

Sunlight exposure

duration

(Hours)

< 6

> 6

28%

72%

0.861

Sunlight exposure

timing

< 09.00

09.00 – 15.00

28%

72%

0.861

Genetic

Yes

52%

28%

0.925

Co-existing

Diasease

None

Preecclampsia

Hyperemesis gravidarum

VSD

Asthma

Big baby

Condylomata acuminata

Anemia

Hepatitis B

56%

16%

0.399

Melasma type

Epidermal

Dermal

Mixed

68%

12%

20%

0.701

MSS

Clean

Mild

Moderate

Severe

24%

20%

36%

20%

0.632

*p<0.05: significant different using Chi Square

Family history with melasma in 25 subjects found

13 people (52%) with positive family history with

melasma, and 12 people (48%) did not get family

history with melasma. In 25 subjects, there were other

coexisting diseases of 4 persons (16%) followed by

hyperemesis gravidarum, congenital heart disease

Ventricular Heart Disease, asthma, large infants,

condylomata acuminate, anemia and hepatitis B. Of

the 25 subjects, the type of melasma epidermal

epidermal (17%), dermal type 3 people (12%) and

mixed type 5 people (20%). The degree of melasma

severity obtained from 25 study subjects was 6 (24%)

clear, 5 (20%) mild, 9 (36%) moderate, and 5 (20%)

severe. Table 1 shows that age, the age of pregnancy,

duration and time of sun-exposure, genetic, co-

existing diseases, type of melasma and MSS

(Melasma Severity Score) showed no significant

difference (p> 0.05).

In Table 2, serum estradiol level in clear group

was 417.80 ± 265.02, the mild group was 836.60 ±

390.89, the moderate group was 793.58 ± 189.87, and

the severe group was 891.00 ± 194.89. Estriol serum

levels obtained on average at the clear group of 94.67

± 93.12, the mild group of 149.88 ± 109.87, the

moderate group of 199.64 ± 46.52, and the severe

group of 141.17 ± 98.69. Based on analysis difference

from table 2, there was a significant different serum

level of estradiol in each group of MSS (p=0.015) and

serum levels estriol did not significantly differ in each

group degrees of MSS (p=0.454).

Comparation of Estradiol and Estriol Serum Levels in Different Degrees of Melasma Severity in Pregnant Women

Table 2:. Average of Serum Estradiol and Estriol Level in

Groups of MSS.

MSS

Estradiol

Estriol

Mean

p-value

Mean

value

Clear

417.80

*0.015

94.67

0.454

Mild

836.60

149.88

Moderat

793.58

199.64

Severe

891.00

141.17

*p<0.05 : signficant different

4 DISCUSSION

Melasma severity score obtained from the average of

25 subjects of the most moderate study (9 subjects),

followed by clear (6 subjects), mild (5 subjects) and

included severe (5 subjects). There were a significant

different serum estradiol levels but not significantly

different serum estriol levels in each MSS group. In

melasma pathogenesis, increased estrogen will bind

to the estrogen receptor on melanocytes thus

stimulating the production of melanin. The increased

estrogen will increase the stimulation of melanin

production so that it is suspected to affect the severity

of melasma. Estrogen levels in pregnant women

dominated by forms of estradiol and estriol

(Dameveska, 2014).

Estrogen receptor (ER) is a steroid hormone

receptor in the cell nucleus. ER has two subtypes

namely ERα and ER-β. Estradiol has a high affinity

that activates both these receptors potentially.

Activation of ER triggers the modulation of

transcription and expression of genes in the

melanocyte. The biologic effects of estradiol, is

considered the most active form of estrogen and has a

high potential for melanogenesis, are mediated by

estrogen-alpha receptors (ER-α), and estrogen-beta

receptors (ER-β) expressed by human skin cells. The

physiological function of estriol is still not fully

understood. Estriol is short-acting estrogen, meaning

it has the lowest affinity for estrogen receptors alpha

and beta compared with estradiol and estrone

(Thornton, 2002).

Although estriol is an estrogen with the lowest

affinity to estrogen receptors compared with

estradiol, several theories mention the mechanism of

action of estriol and estradiol. According to other

literature by Cohen in 1985, said that estriol could

compete with estradiol in binding to estrogen

receptors in the uterus. This relationship evidenced by

the physiological differences in the amount of

estradiol and estriol. Also, physiologically estriol

production is controlled by estradiol production, but

when pregnant estriol production no longer controlled

by estradiol evidenced by high estriol counts until the

end of pregnancy (Cohen, 1985).

In this study, estradiol was significantly different

in each group MSS while estriol was not significant

difference may be due to the affinity of estriol bonds

with estrogen receptors in melanocytes weaker than

the affinity of estradiol bonds with estrogen receptors.

The theory of estradiol and estriol work mechanisms

according to Cohen can also support the results of

research that estradiol has an important role in the

severity of melasma. There is yet another study that

measures serum estriol levels in pregnant women

with melasma so that no data support the results of

this study.

Several weaknesses in this study may be due to

measurement MSS method is done through the

conversion of MASI score measured subjectively

depending on the examiner although it minimised by

involving three examiners. More research is needed

to determine the correlation between serum level

estradiol in each group MSS. Also, melasma is a local

hyperpigmentation disorder of the facial skin so that

research variables may not be able to describe as

taken from serum blood circulation. A

histopathologic study of melasma skin lesions should

be performed.

5 CONCLUSION

In pregnant women with melasma, the serum

estradiol level was significantly different in degrees

of melasma severity, while estriol did not differ.

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Comparation of Estradiol and Estriol Serum Levels in Different Degrees of Melasma Severity in Pregnant Women