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Abstract

Introduction: Melanocytes are cells which are present in the human skin and they are responsible for the melanin production. They can be found in the basal stratum of the epidermis and they have some prolongations extending until the stratum corneum. Melanin synthesis may increase in the presence of some factors and some irregular brownish spots – hyperpigmentations – may appear. Factors which can trigger melanogenesis are excessive sun exposure, hormonal contraception, hormonal reposition therapy, pregnancy, medicines, cosmetics, stress or genetics. Aim: Understanding of the relationship between hormonal contraceptives and hyperpigmentation. Material and Methods: A review of literature study by researching in diverse databases (PubMed, Google Scholar, ScienceDirect and Wiley Online Library). Results/Discussion: According to some authors, estrogenic components which can be found in hormonal contraceptives are associated with hyperpigmentation situations. In the case of progestagenic components, opinions diverge: some studies substantiate that progesterone has the ability to increase melanogenesis and others that it may have the opposite effect of estrogen. In a general way, a few researchers say that hormonal contraceptives affect melanin synthesis while others reject that fact. Conclusion: It is verified the relationship between hormonal contraceptives and hyperpigmentation. However, this topic is not sufficiently well approached, so future investigations are needed to allow its best understanding. Keywords: Hormonal contraceptives; Hyperpigmentation; Estrogen; Progesterone
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HYPERPIGMENTATION ASSOCIATED WITH HORMONAL
CONTRACEPTIVE USE
Rita Peixoto1 & Paula Fonseca*2
1&*2Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Pharmacy Department, Rua 5 de
Outubro, S. Martinho do Bispo, 3046-854 Coimbra, Portugal
Abstract
Keywords: Hormonal
contraceptives;
Hyperpigmentation;
Estrogen; Progesterone
Introduction: Melanocytes are cells which are present in the human skin and they
are responsible for the melanin production. They can be found in the basal stratum of
the epidermis and they have some prolongations extending until the stratum corneum.
Melanin synthesis may increase in the presence of some factors and some irregular
brownish spots hyperpigmentations may appear. Factors which can
trigger melanogenesis are excessive sun exposure, hormonal contraception,
hormonal reposition therapy, pregnancy, medicines, cosmetics, stress or genetics.
Aim: Understanding of the relationship between hormonal contraceptives and
hyperpigmentation.
Material and Methods: A bibliographic review through a research in diverse
databases (PubMed, Google Scholar, ScienceDirect and Wiley Online Library).
Results/Discussion: According to some authors, estrogenic components found in
hormonal contraceptives are associated with hyperpigmentation situations. In the case
of progestagenic components, opinions diverge: some studies substantiate that
progesterone has the ability to increase melanogenesis and others that it may have the
opposite effect of estrogen. In a general way, most researchers say that hormonal
contraceptives affect melanin synthesis; however others reject that fact.
Conclusion: It is verified the relationship between hormonal contraceptives and
hyperpigmentation. However, this topic is not sufficiently well approached, so future
investigations are needed to allow its best understanding.
Introduction
Skin is the biggest multifunctional organ of the human body and it acts as a barrier against ultraviolet (UV)
radiation, microorganisms’ invasions and chemical agents’ penetration. It also controls body fluids loss. The skin is
an organ which is really important in thermoregulation and it also plays an important role in immunological,
sensational and autonomous responses.(1)
The skin is constituted by 3 main layers: the epidermis the exterior layer, the dermis the intermediate layer, and
the hypodermis the most interior and deep layer of the skin. In its turn, the epidermis is divided in 5 subdivisions:
the stratum basale most interior and deep, the stratum spinosum, the stratum granulosum, the stratum lucidum and
the stratum corneum the most exterior. The physic barrier is located mainly in the stratum corneum because on
that stratum there are dead cells keratinocytes -, nucleated epidermal cells and complexes formatted by keratin and
proteins, evolved by a lipid matrix.(2)
Melanocytes are the cells responsible for the production of melanin. They have an important function in skin
protection against the malign effects of UV radiation. They are located in the stratum basale of the epidermis and
they possess extensions until the stratum corneum, where the keratinocytes are. Melanocytes descend from precursor
cells melanoblasts. Melanocytes are responsible for skin tone, which differs from individual to individual
according to its density, number, size and dispersion. Within the melanocytes, melanin is produced by
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Volume 6 (Issue 3): March 2019 ISSN: 2394-9414
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13
melanossomes particles disposed in the cytoplasm of melanocytes, in which melanin is produced. After the
production of melanin, it is transferred to the keratinocytes through the melanocytes’ extensions, where it is
stored.(3,4)
The melanin production happens inside the melanocyte through a process which requires the knowledge of basic
physiology of the human cell as the structural and functional unit of all living beings:
Tyrosinase is the bottom line for all the mechanism which leads to melanin production. It is an enzymatic complex
synthetized in ribosomes and it is transferred to the Golgi complex. In the presence of oxygen, tyrosinase oxidizes
tyrosine (an essential aminoacid) into dihydroxyphenylalanine (DOPA) and then DOPA into dopaquinone. From
this point, the process can take two distinct pathways, depending on the presence or absence of cysteine.
In the absence of cysteine (non-essential aminoacid), dopaquinone is converted into cyclodopa and then cyclodopa
into dopachrome. Dopachrome is degraded by dopachrome tautomerase into dihydroxyindole (DHI), in greater
proportion, and into dihydroxyindole-2-carboxylic acid (DHICA), in minor. Tyrosinase then oxidizes DHICA into
eumelanin.
In the presence of cysteine, dopaquinone reacts with it and forms cysteynildopa, which is oxidized into
benzothiazinic intermediates, which produce pheomelanin. This process goes on while cysteine is present. When it
finishes, it starts the process of production of eumelanin.(3,5)
Figure 1.
Melanin production process (L-DOPA L-3,4-dihydroxyphenylalanine; Trp-2 tyrosinase-related protein-2; Trp-1
tyrosinase-related protein-1; DHICA dihydroxyindole-2-carboxylic acid; DHI dihydroxyindole) Source: Uyen et al,
2005
Individual with a darker skin have a bigger production of eumelanin (darker pigment); those with a lighter skin have
a bigger production of pheomelanin (lighter pigment). Eumelanin diffuses UV radiation, attenuates its penetration
on skin and reduces its harmful effects, so people with darker skins can get tanner without getting burned.
Pheomelanin generates free radicals in response to UV radiation and it is capable of causing damage in
deoxyribonucleic acid (DNA), so people with lighter skins present higher risk of epidermal damage induced by UV
radiation. Skin and hair colour result from the mixture of both melanins.(3,4)
As a response to diverse stimulus, melanin synthesis may increase so there may appear some irregular brownish
marks, especially in the areas exposed to sun radiation. Those areas are called hyperpigmented areas. Two common
problems are melasma and post-inflammatory hyperpigmentation. The most prevalent situation is melasma, which is
characterized by marks which appear on the face. Within other pathologies that consist on hyperpigmentations, there
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can be found the following: periorbital hyperpigmentation, Riehl’s melanosis, exogenous ochronosis, dermatosis
papulosa nigra, lentigo, lichen planus pigmentosus and freckles.(6,7)
The most affected areas ate the forehead, the temples and the cheeks. This phenomenon affects mainly women on
fertile age. Meanwhile, it can also affect men, although they represent 10% of all cases. The appearance of these
cutaneous manifestations happens due to excessive sun exposure, hormonal contraception, hormonal reposition
therapy, pregnancy, medicines, cosmetics or stress, and there is also a genetic component associated with this
outcoming, with a probability around 40-60%.(3,8-12)
Among the medicines that can cause hyperpigmentation there are antimalarial, amiodarone, cytotoxic, minocycline,
chlorpromazine, tricyclic antidepressives and anticonvulsants. Hyperpigmentation develops slowly. The first marks
and visible only months or even years after the taking.(11)
The responsible genes for human pigmentation differ from population to population and inside the population,
resulting on a different production of melanin and, consequently, on a bigger or smaller manifestation of cutaneous
hyperpigmentations.(13)
Deep down, melanin confers some protection to the skin because of its ability to absorb UV radiation and it also has
antioxidant properties once it eliminates free radicals. Besides UV radiation, nowadays it is known that visible
spectrum light may also have potential to cause hyperpigmentations, at least on the individuals with darker skin.(14,15)
In the case of hormonal contraception, it is used for about 60% of women with ages between 16 and 30 years old. At
first, contraceptives contained only progesterone; however, as time went by, there were seen a few undesirable
androgenic effects, so it was introduced estrogen to the contraceptives. Nowadays, combined hormonal
contraceptives are a very effective method of undesirable pregnancy prevention when used properly.(12,16)
There are some hormonal contraceptive methods like oral contraception, vaginal ring, transdermal patch, intra
uterine device, subcutaneous implant and injectable contraceptive. It is estimated that around 10 to 20% of women
who use contraceptives develop this kind of marks. There are several studies about the area and it appears that the
cause of this cutaneous expressions derives from the fact that most contraceptives contain estrogen in its
composition. There are two types of estrogenic receptors which measure the biologic responses of estrogen in the
human body. One of its responses may be the increase of melanogenesis.(12,16-18)
So, the problem to approach is the possibility that the hormones contained in the hormonal contraceptives may be or
may not be a potential cause of hyperpigmentations.
Materials and methods
This study is a bibliographic review, effectuated between September 2017 and May 2018. For this research, there
were analysed free-access articles retrieved from online databases (PubMed, Google Scholar, ScienceDirect and
Wiley Online Library), with the support of software and computer equipment. The articles had language restriction
for Portuguese, English, Spanish and Polish and the keywords searched were “hormonal contraceptives”,
“hyperpigmentation”, “estrogen”, “progesterone”, “melanin” and “pigmentation”.
Inclusion criteria to use the articles found were:
-Study of the relationship between the use of hormonal contraceptives and the emergence and/or aggravation of
hyperpigmentation situations;
-Date of publication in the last 10 years (2008-2017).
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Results and discussion
Given the theme under study, the research focused on bibliographical sources which debate the hypothesis that
steroid hormones contained in the hormonal contraceptives constitute a potential to emerge and/or aggravate
hyperpigmentations. Therefore, the presented review is focused on the demystification of that conjecture.
1. Estrogenic components
Sun et al., in 2017, determined through an in vitro study that estrogen promotes melanogenesis both in the skin and
in the hair. This study allowed to conclude that women who take oral contraceptives which contain estrogen are
more disposed to the development of cutaneous hyperpigmentations. It was discovered that UV radiation increases
the proliferation of melanocytes, so it is a factor which upholds the effect of estrogen.(19)
According to Tamega et al., estradiol present in the hormonal contraceptives causes, in a dose-dependent way, the
increase of the activity of tyrosinase and dopachrome tautomerase, with the subsequent decrease of the proliferation
of the melanocytes. This study in vitro was carried in the year of 2015, using samples of healthy cutaneous tissue
and tissue affected by hyperpigmentations. The authors discovered that estradiol increases ribonucleic acid (RNA)
levels of the melanocortin receptors type 1 (MCR-1), which is evolved in the regulation of melanin synthesis. The
increase of MCR-1 expression is responsible for a higher activity of the keratinocytes, leading to a bigger production
of melanin. These authors try to approach the way progesterone acts by the level of melanogenesis; however, the
research is inconclusive so they appeal to the need of more studies.(20)
Following Cohen, in 2017, estrogenic receptors - α and β - are both over-expressed in a hyperpigmented skin when
compared to a normal skin. This fact happens due to the presence of high levels of estrogen. Estrogen, as referred
by other authors, increases melanogenesis through stimulation of some proteins: tyrosinase, tyrosinase-related
protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2) and melanogenesis associated transcription factor (MITF).
On a microscopic exam performed on a hyperpigmented skin, it was possible to verify that the melanocytes were
bigger and more prominent; yet, there weren’t more than before. Meanwhile, Asian women with
hyperpigmentations in the face were evaluated as its lesions showed that melanin was more dispersed for all the
epidermis but also a numeric increase of melanocytes, melanin and melanossomes.(21)
As studied by Kim et al. in 2012, estrogen may induce the expression of PDZ domain containing 1 (PDZK1). This
protein is clinically related to melasma. In this study there were used monocultures and co-cultures of melanocytes
and keratinocytes with and without over-expression of PDZK1 form 15 individuals. The administered estrogen
caused an increase of PDZK1 expression. This protein increases tyrosinase’s activity and the transfer of melanin
from melanossomes to keratinocytes. PDZK1 inhibition reduced tyrosinase’s expression through regulation of the
activity of α and β estrogen receptors. The authors also verified that hyperpigmented cells had a higher expression
of PDZK1 in comparison to normal cells.(22)
According to Lee, on a systematic review from 2015, melanogenesis induction by estrogen may occur through
PDZK1 expression and may be associated to cyclic adenosine monophosphate (cAMP) cascade activation, once
estrogen increases cAMP levels and the expression of tyrosinase and MITF.(23)
Mahmood et al., on their research from year 2011, quote some studies in vitro which prove that melanocytes
express estrogenic receptors and that estrogen increases levels of tyrosinase, TRP-1 and TRP-2 (Figure 2). The
connection of melanocytes stimulation hormone (MSH) to MCR-1 receptors mediates melanogenesis which occur
naturally in the human being. In the presence of estrogen, the expression of MCR-1 and tyrosinase increase, leading
to an augmented melanogenesis.(24)
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Figure 2.
Mechanism evolved on melanogenesis induced by estrogen (ER estrogen receptor; PDZK1 PDZ domain containing 1;
NHE3 sodium-hydrogen antiporter 3; CFTR - Cystic fibrosis transmembrane conductance regulator; TYR - tyrosinase;
TRP1 tyrosinase-related protein-1; TRP1 tyrosinase-related protein-2; MITF melanogenesis associated transcription
factor)
Source: Lee, 2015
In short: All the previously quoted authors associate estrogenic components in hormonal contraceptives with
hyperpigmentation situations. Sun et al. also allege that UV radiation is an aggravating factor. Tamega et al. and
Mahmood et al. studied the evolvement of MCR-1 receptors in melanogenesis. PDZK1 is over-expressed in
hyperpigmented cells, as described for Lee and Kim et al. The implication of TRP-1 and TRP-2 is also evident, as
studied for Cohen.
2. Estrogenic and progestagenic components
A cross-sectional study accomplished by Damayanti et al. in 2017, with a sample of 17 female individuals, allowed
to associate the continuous use of oral combined contraceptives with the appearance of hyperpigmentations. They
have concluded that women who took those contraceptives for at least 2 years have suffered the adverse effect on
approach: hyperpigmentations. The authors determine that a period of three months of oral combined contraceptives
may be enough to start mechanisms which can lead to hyperpigmentation.(25)
A review study done by Gardini et al. in the year of 2011 allowed to associate the progression of a
hyperpigmentation situation to an oncological situation of melanoma. The authors close the article concluding that
the use oral contraceptives only containing estrogen or containing a combination of estrogen and progesterone
increase melanin production and the number of melanocytes. However, those don’t increase the risk for developing
melanoma.(26)
Following Wiedemann et al., on a study in vitro on melanocytes in 2009, estrogen and progesterone caused its
multiplication and increased tyrosinase’ activity on three from eight cell cultures. Still, when they studied the effects
of progesterone isolated, there wasn’t any increase of tyrosinase but there was a decrease of the amount of melanin.
Therefore, the authors conclude that progesterone present in hormonal contraceptives may have an inhibitory effect
on the proliferation of melanocytes.(12)
An in vitro study realized in 2016 allowed to Natale et al. to associate ethinylestradiol which is present in hormonal
contraceptives with melanin production. The process that occurs naturally to form melanin is regulated by MSH. As
referred by other authors, MSH links to MCR-1, activating adenylcyclase and increasing cAMP. This molecule
triggers a cascade of events required to melanin synthesis. Women who use hormonal contraceptives keep this
process dependent of MSH. Nevertheless, after in vitro evaluation of the behaviour of melanocytes which had been
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treated with estrogen, melanin synthesis increased in about 208%, without affecting the number or density of
melanocytes. The authors also evaluate the production of melanin when progesterone was administered. They
concluded that progesterone has the opposite effect of estrogen, diminishing melanin production in about 58%. So,
the conclusion of this study leaves the possibility that, in the case of use of hormonal combined contraceptives, the
stimulatory effects of estrogen can be antagonized by the presence of progesterone.(27)
According to Hyun Jang et al., in 2012, estrogen and progesterone are related to hyperpigmentation. Estrogen
interacts and activates α and β estrogenic receptors. The expression of β-estrogenic receptor is predominant in case
of lesion of melanocytes. This discover suggests that estrogen and its analogues, by interacting with this receptor,
play an important role on physiology and physiopathology of the melanocyte. As for progesterone, the researchers
assume that it stimulates melanogenesis in the melanocytes, although they say that its function, as said for other
studies, inhibits melanogenesis.(28)
An in vitro study conducted by Jang et al. in 2010 consisted in comparing the expression of estrogenic and
progestagenic receptors between hyperpigmented areas and non-affected areas from the faces of individuals with
melasma. All the participants were female and had been suffering from the problem for at least 8 years. Although
the protective effects of estrogen against skin aging, the authors allege that estrogen increases melanin activity,
inducing skin pigmentation. Between the two estrogen receptors already mentioned, the β-estrogenic receptor is the
predominant one on the lesions of melanocytes. Results indicate a higher activity of those receptors in skins affected
by melasma on the epidermis, essentially on stratum basale and stratum spinosum, on which β-estrogenic receptors
present a greater immunoreactivity than those on stratum granulosum. There wasn’t found any specific expression of
receptors in affected skin, neither in the surrounding healthy tissues. As for progesterone receptors, its expression
was also higher in skin with lesions. Therefore, investigators prove that the melanin amount present in skin affected
by melasma was superior in comparison to non-affected skin and they associate positively hormonal receptors like
estrogenic and progestagenic with skin lesions derived from melasma.(29)
In short: Through the analysis of precious data, it is understandable that according to Damayanti et al., Gardini et
al., Hyun Jang et al. and Jang et al. estrogen and progesterone both possess ability to increase melanogenesis.
However, Wiedemann et al. and Natale et al. say that only estrogen presents stimulatory effects of melanogenesis
and that progesterone could have the opposite effect of estrogen.
3. Unknown components
In 2015, Pietrzak et al. observed that long term use of hormonal contraceptives increases the amount of
melanossomes in melanocytes, increases its metabolism and, as a consequence, increases melanin production. The
authors suggest that exposure to UV radiation may rise the risk of development of hyperpigmentations.(30)
As studied by Krupashankar & Somani in the year of 2014, with the aim of evaluating the epidemiology of melasma
associated with diverse factors (including oral contraceptive use), 266 women with melasma were evaluated, from
which only 23 (8,6%) had taken oral contraceptives. 7 of them took it for 1 to 3 years. This way, the authors
conclude that there is no statistically significant relationship; meanwhile, they appeal to the need for more studies
around the subject.(31)
A case-control study performed in women in 2009 by Applebaum et al. allowed to make an association between oral
contraceptive use and the prevalence of squamous cell carcinoma (SCC). In this study, the authors recognize that
oral contraceptive taking changes cell response to exposure to UV radiation, making it more susceptible to its
effects. From 261 cases and 298 controls, only 7 cases and 4 controls had experienced melasma and the duration of
oral contraceptive use was equal in women who had not had that experience. In other words, from women who took
oral contraceptives for the same time, only a few developed hyperpigmentations. This fact lead the investigators to
conclude that hormonal contraceptive use is not statistically related to hyperpigmentation.(32)
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In a case-control study 312 individuals with hyperpigmentation in the face were evaluated, in the year of 2011. 250
individuals were female and 62 were male. From all women included in the study, only 18,4% took oral
contraceptives during the follow-up period. Results show that there is no significant relationship between taking oral
contraceptives and the appearance or aggravation of hyperpigmentation. However, this study only had a follow-up
period of one year (January 2009 to December 2009), so the effects of estrogen may not have been perceptible
within this range.(33)
According to an observational study of Guinot et al. from year 2010, with a sample of 197 individuals, from which
188 were female, oral contraceptives are effectively a factor which interferes with the appearance of
hyperpigmentations in the face. 135 women had never used oral contraceptives, 40 had used but discontinued its use
and the other 13 were still taking it. The authors conclude that oral contraceptives constitute a triggering factor in
26% of all cases and aggravating factor in 38%. Yet, the severity level of lesions varies according to ethnic group.
Melasma arises 1 to 3 years after the first taking and disappears slower than marks triggered by pregnancy (some
marks never disappear totally). In this study, the investigators say that melasma represents about two thirds of all
cutaneous secondary effects of oral contraceptives.(34)
In short: Most studies in this category reject the hypothesis that hormonal contraceptives implicate
hyperpigmentation situations, as described by Krupashankar & Somani, Applebaum et al. and Rathi & Achar. On
other hand, Pietrzak et al. and Guinot et al. found a relationship between hormonal contraceptives use and the
appearance and/or aggravation of hyperpigmentations. One aspect to point in these studies conducted by
Krupashankar & Somani and Rathi & Achar is the low number of women who took hormonal contraceptives in
comparison to the total of women in the sample.
Conclusion
After the present research, it is concluded that hormonal contraceptives use is related to the appearance and/or
aggravation of hyperpigmentation situations.
Although some authors conclude that estrogen present in hormonal contraceptives doesn’t have a statistically
significant relationship with the object of study, most studies substantiate that there is a cause-effect relationship.
The role of progesterone is not yet entirely clarified, once there are some studies which point its synergic potential
with estrogen while others mention its antagonist and protective action from the cutaneous effects of estrogen.
About the population studies, it is important to remark that tiny samples and/or restricted follow-up periods will not
allow the obtaining of reliable results.
Another limit on the found studies was the fact that the main problem of hyperpigmentation is melasma. As for the
remaining pathologies associated to hyperpigmentations, the information is quite reduced.
Therefore, it is verified the positive association between hormonal contraceptive use and hyperpigmentation.
However, the achievement of profitable articles for this study was an arduous task because the existing studies are
still rare. It becomes necessary to deepen studies about the role of progesterone and other diseases caused by
hyperpigmentations. The relationship between hormonal contraceptives and hyperpigmentation is a subject which
needs future investigations so that it can be fully demystified.
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Article
Full-text available
Background Melasma is a chronic acquired focal hypermelanosis affecting photoexposed areas, especially for women during fertile age. Several factors contribute to its development: sun exposure, sex steroids, medicines, and family history. Melanic pigmentation pathway discloses several SNPs in different populations. Here, we evaluated the association between genetic ancestry and facial melasma. MethodsA cross-sectional study involving women with melasma and an age-matched control group from outpatients at FMB-Unesp, Botucatu-SP, Brazil was performed. DNA was extracted from oral mucosa swabs and ancestry determined by studying 61 INDELs. The genetic ancestry components were adjusted by other known risk factors by multiple logistic regression. ResultsWe evaluated 119 women with facial melasma and 119 controls. Mean age was 39 ± 9 years. Mean age at beginning of disease was 27 ± 8 years. Pregnancy (40%), sun exposure (37%), and hormonal oral contraception (22%) were the most frequently reported melasma triggers. All subjects presented admixed ancestry, African and European genetic contributions were significantly different between cases and controls (respectively 10% vs 6%; 77% vs 82%; p < 0.05). African ancestry (OR = 1.04; 95% CI 1.01 to 1.07), first generation family history (OR = 3.04; 95% CI 1.56 to 5.94), low education level (OR = 4.04; 95% CI 1.56 to 5.94), and use of antidepressants by individuals with affected family members (OR = 6.15; 95% CI 1.13 to 33.37) were associated with melasma, independently of other known risk factors. Conclusions Facial melasma was independently associated with African ancestry in a highly admixed population.
Article
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Significance: The skin is a complex and dynamic organ that performs several vital functions. The maturation process of the skin starts at birth with the adaption of the skin to the comparatively dry environment compared to the in utero milieu. This adaptive flexibility results in the unique properties of infant skin. To deliver appropriate care to infant skin, it is necessary to understand that it is evolving with unique characteristics. Recent Advances: The role of biophysical noninvasive techniques in the assessment of skin development underlines the importance of an objective evaluation of skin physiology parameters. Skin hydration, transepidermal water loss, and pH values are measurable with specific instruments that give us an accurate and reproducible assessment during infant skin maturation. The recording of these values, following standard measurement procedures, allows us to evaluate the integrity of the skin barrier and to monitor the functionality of the maturing skin over time. Critical Issues: During the barrier development, impaired skin function makes the skin vulnerable to chemical damage, microbial infections, and skin diseases, possibly compromising the general health of the infant. Preterm newborns, during the first weeks of life, have an even less developed skin barrier and, therefore, are even more at risk. Thus, it is extremely important to evaluate the risk of infection, skin breakdown, topical agent absorption, and the risk of thermoregulation failure. Future Directions: Detailed and objective evaluations of infant skin maturation are necessary to improve infant skin care. The results of these evaluations should be formed into general protocols that will allow doctors and caregivers to give more personalized care to full-term newborns, preterm newborns, and infants.
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Estrogens are widely used in hormone replacement therapy, gynecology, urogynecology and rarely in dermatology. Non-therapeutic use of estrogens is very widespread. Estrogens are used as contraceptives, which cause a lot of serious side effects. A common clinical problem is skin hyperpigmentation (melasma), occurring mainly in women who take contraceptives with high doses of estrogens. But low doses of estrogens may also cause skin side effects. The mechanism of melasma development is very complicated and not fully understood. It is very likely that UV radiation and genetic background can affect melasma development. Effective therapy should lead to prevention or alleviation of relapses. Treatment should also reduce the area of lesions and improve the appearance of skin. There is no effective and universal pattern of treatment, in which only one substance or method is used. A combination of different methods is used to optimize the therapy. An important role is attributed to prevention, especially protection from UV radiation.
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The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.
Article
Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti-estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel--topically administered--therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor.
Article
Objective: This study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis. Methods: GPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry. Results: Upregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin. Conclusion: GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.
Article
Background: Melasma is a commonly acquired hypermelanosis of facial skin due to various etiological factors including hormonal imbalance. Objectives: To find out the relationship between hormonal imbalance and melasma in females. Patients and methods: One hundred and fifty female patients suffering from melasma, between the ages of 17-45 years, were enrolled in the study. They were examined by Wood's lamp to see the type of melasma whether epidermal, dermal or mixed (dermoepidermal). Patients were investigated for levels of estrogen, progesterone and prolactin in two consecutive follicular and luteal phases on 9 th and 18 th day of cycle, respectively. Forty control cases were also investigated for the aforementioned hormonal levels in their follicular and luteal phases. Results: Out of 150 patients, 138 completed the study while 12 patients were lost to follow up. Amongst the 138 evaluable patients, there were only 4 patients who had normal values for all the three hormones i.e. estrogen, progesterone and prolactin in all four phases. Fifteen patients (10.9%) had normal values of estrogen in both follicular (F1 & F2) and luteal phases (L1 & L2) while the remaining 123 patients (89.1%) had deranged values of estrogen (mostly increased) in any of the four phases. The values of progesterone were normal in 62 (44.9%) patients while they were deranged in 76 (55.1%) patients in all four phases. The levels of prolactin were normal in 134 (97.1%) patients while deranged in 4 (2.9%). Out of 40 controls, only 3 (7.5%) had increased values of estrogen in both follicular and luteal phases. Conclusion: Estrogen is found to be the causative agent of melasma.
Article
Melasma is a common skin pigmentation condition. Given therapeutic difficulty as one of the biggest concerns, understanding of the etiology and pathogenesis of melasma becomes essential. UV irradiation, female sex hormones, and inflammatory processes are addressed as triggering factors with genetic predisposition. The mechanism of UV-induced melanogenesis has been extensively investigated as a model system to study melasma pathogenesis. Hitherto, treatment modalities for melasma are similar to other hyperpigmentation disorders. However, individual triggering factors induce a separate pigmentation disease, whose pathogenic mechanisms and clinical phenotypes are different from the ones encountered in melasma. Fortunately, there have been ongoing updates on melasma pathogenesis with regard to major triggering factors. Presence of certain factors working independently of UV exposure and role of dermal factors and microRNAs are being identified as novel discoveries about melasma pathogenesis. In this review, the melasma pathogenesis is reviewed in association with updated and new findings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Objective Compare gene and protein expression for estrogen receptor β (ER-β) and progesterone receptor (PR) in facial melasma and adjacent healthy skin.MethodsA cross-sectional study including 42 women with facial melasma, conducted at the Dermatology Service of Botucatu Medical School of São Paulo State University, Brazil. Biopsies of the melasma skin were performed, together with healthy surrounding skin. The gene expression (real-time PCR) of the hormone receptors in the tissue was evaluated. Subsequently, skin fragments were immunostained for nuclear ER-β and PR, evaluated according to their HSCORE (epidermis) and percentage of staining per microscopic field (dermis).ResultsMessenger RNA tissue expression for ER-β and PR showed no difference between melasma affected skin fragments and the healthy perilesional areas (p>0.2). Median nuclear epithelial expression for ER-β and PR was higher in lesioned skin (HSCORE 157 and 58) than in the healthy perilesional skin (HSCORE 97 and 19; p<0.01), with no difference in dermal immunostaining. Nuclear histological expression for ER-β was associated to sun induced melasma and negative familiar background; PR expression was associated to sun induced melasma and darker phototypes.Conclusion No difference was observed in gene expression for estrogen β and progesterone receptors in melasma-affected skin compared with adjacent healthy skin. However, the higher protein expression of these receptors in melasma-affected epithelia suggests hormonal participation in the pathogenesis of this disease.This article is protected by copyright. All rights reserved.