No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The Phytoestrogenic Effect of Daidzein in Human Dermal Fibroblasts
Abstract
Estrogen deficiency results in a reduction of skin quality and function in postmenopausal women. Over the past decade, many studies have supported that estrogen provides anti-aging effects as a result of the ability of estrogen to prevent skin collagen decline, restore skin elasticity, and increase skin hydration in postmenopausal women skin. Due to their structural similarity with estrogen, isoflavones have been called phytoestrogens. Photoprotective effects of isoflavones are well established while their estrogenic-like activities are not fully understood in human skin. In this study, we investigated whether daidzein, an effective isoflavone, has phytoestrogenic activity and induces transcriptional change of extracellular matrix components in dermal fibroblasts. We examined the luciferase activity of daidzein and {\beta}-estradiol using transiently transfected NIH3T3-ERE cells. The estrogenic receptor-dependent transcriptional activity was increased in a dose-dependent manner when treated with daidzein, with a maximum of 2.5-fold induction at 10?g/mL of daidzein compared with non-treated control. In addition, daidzein significantly in creased the expressions of collagen type I, collagen type IV, elastin, and fibrillin-1 in human dermal fibroblasts. By comparing with the effects of {\beta}-estradiol through out all the experiments, we confirmed that daidzein had estrogenic activity and function in fibroblasts. These results suggest that daidzein-based application, having both photoprotective and phytoestrogenic effects, may be a powerful approach for skin anti-aging of postmenopausal women.
... This pharmacological activity is attributed to various metabolites including equol and trihydroxy isoflavone (Meng-Yao et al., 2016). Kim, Hong, and Lee (2014) investigated whether daidzein, a potent isoflavone, displays phytoestrogen activity and induces transcriptional changes in extracellular matrix components in dermal fibroblasts. The estrogenic receptor-dependent transcriptional activity increased in a dose-dependent manner when treated with daidzein, with a maximum of 2.5-fold induction at 10 μg/mL of daidzein compared with the nontreated control. ...
... Phytoestrogens can protect the skin from oxidative stress: (1) They bind to ERβ and activate ERE to promote the dissociation of Nrf2 and Keap1. Nrf2 enters the nucleus and activates ARE, which enhances the transcription of antioxidant enzymes (Kim et al., 2014); and (2) They can improve mitochondrial membrane potential and increase NO release under physiological conditions. They can also hinder the decrease in mitochondrial membrane potential and the increased NO release caused by H 2 O 2 . ...
Skin undergoes degenerative changes as it ages, which include the loss of elasticity, reductions in the epidermal thickness and collagen content, elastic fiber degeneration, and increased wrinkling and dryness. Skin aging can be significantly delayed by the administration of estrogen. Estrogen deficiency following menopause results in atrophic skin changes and the acceleration of skin aging. Estrogen administration has positive effects on human skin by delaying or preventing skin aging manifestations, but the use of estrogen replacement is a risk factor for breast and uterine cancer. Phytoestrogens are a large family of plant‐derived molecules possessing various degrees of estrogen‐like activity; they exhibit agonist or antagonist estrogenic properties depending on the tissue. These molecules could be ideal candidates to combat skin aging and other detrimental effects of hypoestrogenism. In this paper, we review the effects of phytoestrogens on human skin and the mechanisms by which phytoestrogens can alleviate the changes due to aging.
... It is known that extracellular matrix (ECM) components, including collagen and elastic fibers, which are responsible for the structural and elastic qualities of the skin, decrease with age. Mi-Sun et al. found that daidzein, similarly to β-estradiol, significantly increases the mRNA expression of collagen types I and IV, elastin, and fibrillin-1 in normal human dermal fibroblasts (NHDFs) [72]. Zhao et al. also observed that daidzein treatment increases collagen synthesis and inhibits collagen degradation in daidzein-treated fibroblasts and mouse skin. ...
Isoflavones are found in numerous plant species within the Leguminosae family; however, soy isoflavones are particularly significant in practice and have been extensively studied in recent years. The health-promoting potential of orally administered soy isoflavones is widely documented in the scientific literature, and many review articles have been developed to highlight their significance. However, it should be noted that soy-isoflavone-rich extracts and isolated soy isoflavones, such as genistein and daidzein, are also often applied topically as ingredients in many formulations, including face creams, tonics, and emulsions. New delivery systems are continuously being developed to enhance the skin permeability of isoflavones, thus improving their efficacy. In this context, their direct activity on skin cells is an important aspect of scientific research. The anti-inflammatory, protective, and antioxidant properties of isoflavones and soy extracts make them promising cosmetic ingredients with anti-aging potential because inflammation and the accumulation of reactive oxygen species (ROS) can lead to structural and functional changes in skin cells, accelerating the aging process. This review provides an overview of research on the impact of the application of soy isoflavone extract and soy-derived isoflavones on skin cells, with a focus on the documented molecular mechanisms underlying their effects. This study aims to offer essential insights to aid in the development of functional cosmetics and future clinical applications.
... Sun et al., 2016). It has phytoestrogen activity and induces transcriptional changes in extracellular matrix components in dermal fibroblasts (Kim et al., 2014). The estrogenic receptor-dependent transcriptional activity increased in a dose-dependent manner when treated with daidzein, with a maximum of 2.5-fold induction at 10 μg/mL of daidzein compared with the nontreated control. ...
Polyphenolic compounds constitute a diverse group of natural components commonly occurring in various plant species, known for their potential to exert both beneficial and detrimental effects. Additionally, these polyphenols have also been implicated as endocrine-disrupting (ED) chemicals, raising concerns about their widespread use in the cosmetics industry. In this comprehensive review, we focus on the body of literature pertaining to the estrogenic properties of ED chemicals, with a particular emphasis on the interaction of isoflavones with estrogen receptors. Within this review, we aim to elucidate the multifaceted roles and effects of polyphenols on the skin, exploring their potential benefits as well as their capacity to act as ED agents. By delving into this intricate subject matter, we intend to provoke thoughtful consideration, effectively opening a Pandora’s box of questions for the reader to ponder. Ultimately, we invite the reader to contemplate whether polyphenols should be regarded as friends or foes in the realm of skincare and endocrine disruption.
... In the cosmetic industry, extracts containing soy isoflavones (especially aglycones, such as genistein and daidzein) are particularly desirable because of their ability to delay skin aging by inhibiting collagen degradation and increasing the levels of transforming growth factor β (TGF-β). The last process is responsible for the production of an extracellular matrix and stimulates fibroblast proliferation [5,6]. In addition, isoflavones display antioxidant activity. ...
Soybeans are commonly known as a valuable source of biologically active compounds including isoflavones as well as allantoin and alpha-hydroxy acids. Since these compounds exhibit skin therapeutic effects, they are widely used in the cosmetic and pharmaceutical industries. The presented paper shows the optimization of three solvent systems (ethanol, water, and 1,3-propanediol) to increase the extraction efficiency of isoflavones (daidzin, genistin, 6″-O-malonyldaidzin, 6″-O-malonylglycitin, 6″-O-malonylgenistin), allantoin, and alpha-hydroxy acids (citric acid, malic acid) from soybean leaves. A simplex centroid mixture design for three solvents with interior points was applied for the experimental plan creation. Based on the obtained results of metabolite extraction yield in relation to solvent composition, polynomial regression models were developed. All models were significant, with predicted R-squared values between 0.77 and 0.99, while in all cases the model's lack of fit was not significant. The optimal mixture composition enabling the maximization of extraction efficiency was as follows: 32.9% ethanol, 53.9% water, and 13.3% propanediol (v/v/v). Such a mixture composition provided the extraction of 99%, 91%, 100%, 92%, 99%, 70%, 92%, and 69% of daidzin, genistin, 6″-O-malonyldaidzin, 6″-O-malonylglycitin, 6″-O-malonylgenistin, allantoin, citric acid, and malic acid, respectively. The solvent mixture composition developed provides a good extraction efficiency of the metabolites from soybean leaves and high antioxidant properties.
... Saat hyaluronidase meningkat maka dapat menyebabkan kerutan tanda penuaan dan dapat diinhibisi menggunakan antioksidan [29], [30]. [19], [35]. Daidzein berpotensi lebih baik dalam menghambat enzim hyaluronidase dan sebagai antioksidan, memiliki dua mekanisme dalam menghambat radikal bebas yang meningkatkan aktivitas enzim antioksidan [12]. ...
AbstrakProses penuaan pada kulit dapat meliputi hilangnya elastisitas, degenerasi serat elastis, pengurangan kandungan kolagen dan ketebalan epidermis, peningkatan kerutan dan kondisi kulit yang semakin kering. Perawatan kulit salah satunya dengan menggunakan produk anti-aging yang dapat memperlambat proses penuaan. Salah satu tanaman yang dapat digunakan sebagai bahan aktif produk anti-aging ialah kedelai yang mengandung beberapa komponen fungsional seperti asam fenolat, flavonoid, isoflavonoid (quercetin, genistein, dan daidzein), s-equol, tannin dan proantosianidin serta vitamin E yang merupakan antioksidan untuk melawan radikal bebas sehingga menghambat terjadinya oksidasi, penuaan kulit dan mengurangi kerusakan sel. Tujuan pembuatan review artikel ini ialah memberikan informasi mengenai efektivitas sari kedelai sebagai anti-aging dalam kosmetik. Metode penulisan review artikel ini ialah metode penelitian komparatif dengan mempelajari artikel mengenai sari kedelai fermentasi dan non fermentasi untuk anti-aging dalam kosmetik. Hasil review dari beberapa artikel dikatakan bahwa sari kedelai fermentasi dan non fermentasi yang mengandung isoflavon genistein dan daidzein memiliki efektifitas yang baik untuk digunakan sebagai anti-aging. Polifenol isoflavon mengandung gugus hidroksil fenolat yang berinteraksi dengan ROS dan menghambat aktivitasnya sehingga proses penuaan dapat diperlambat. Selain itu, ekstrak kedelai fermentasi dan non fermentasi dapat digunakan sebagai antioksidan, pelembab, anti keriput dan anti inflamasi. Kata kunci: Anti-aging, Fermentasi, Kedelai, Kosmetik
... Many people believe that phytoestrogens can protect the skin from oxidative stress by binding to ERβ and activating ERE, to cause the dissociation of Nrf2 and Keap1. Nrf2 enters the nucleus and activates ARE, which increases the transcription of antioxidant enzymes [39]. This increases mitochondrial membrane potential and stimulates NO release in physiological circumstances. ...
It has been previously demonstrated in light microscopic and immunohistochemical studies that ovariectomized rats receiving young coconut juice at 100 mL/kg BW showed much better wound healing and improved skin complexion. Nevertheless, it was found that young coconut juice at 100 mL/kg BW/day caused unfavorable side effects, such as glycogen deposition in the liver. Therefore, in the current study, 3 lower doses (10, 20, and 40 mL/kg BW/day) were optimized, and the ultrastructure was further investigated. Compared to normal rats, all the parameters regarding skin changes, including epidermal and dermal thickness, the number of hair follicles, the diameters of collagen fibrils, perimeters, and nuclei of fibroblast and keratinocyte cells, and ultrastructural changes in keratinocyte and fibroblast cells were significantly reduced in ovariectomized rats. Those parameters in the ovariectomized rats were restored to normal by injecting estradiol benzoate or by feeding young coconut juice to the rats, where the effect was found to be dose-related but not in the case of all the parameters. In most cases, a dose of young coconut juiceof 40 mL/kg BW/day was the optimal dose. The results suggest that young coconut juice may be as effective as estradiol benzoate in reducing skin atrophy/aging, probably as a selective estrogen receptor moderator.
Aging is the result of the accumulation of a wide variety of molecular and cellular damages over time, meaning that “the more damage we accumulate, the higher the possibility to develop age-related diseases”. Therefore, to reduce the incidence of such diseases and improve human health, it becomes important to find ways to combat such damage. In this sense, geroprotectors have been suggested as molecules that could slow down or prevent age-related diseases. On the other hand, nutraceuticals are another set of compounds that align with the need to prevent diseases and promote health since they are biologically active molecules (occurring naturally in food) that, apart from having a nutritional role, have preventive properties, such as antioxidant, anti-inflammatory and antitumoral, just to mention a few. Therefore, in the present review using the specialized databases Scopus and PubMed we collected information from articles published from 2010 to 2023 in order to describe the role of nutraceuticals during the aging process and, given their role in targeting the hallmarks of aging, we suggest that they are potential geroprotectors that could be consumed as part of our regular diet or administered additionally as nutritional supplements.
Isoflavones exist in nature predominantly as glucosides such as daidzin or genistin and are rarely found in their corresponding aglycone forms daidzein and genistein. The metabolism and absorption of isoflavones ingested with food is well documented, but little is known about their use as topical photo-protective agents. The aim of this study was to investigate in a comparative analysis the photo-protective effects of isoflavones in both their aglycone and glucoside forms. In human skin fibroblasts irradiated with 60 mJ/cm2 ultraviolet B (UVB), we measured the expression levels of COX-2 and Gadd45, which are involved in inflammation and DNA repair, respectively. We also determined the cellular response to UVB-induced DNA damage using the comet assay. Our findings suggest that both the isoflavone glucosides at a specific concentration and combination with an aglycone mixture exerted an anti-inflammatory and photo-protective effect that prevented 41% and 71% of UVB-induced DNA damage, respectively. The advantages of using either isoflavone glucosides or an aglycone mixture in applications in the field of dermatology will depend on their properties and their different potential uses.
Soybeans are rich in immuno-modulatory isoflavones such as genistein, daidzein, and glycitein. These isoflavones are well-known antioxidants, chemopreventive and anti-inflammatory agents. Several epidemiological studies suggest that consumption of traditional soy food containing isoflavones is associated with reduced prevalence of chronic health disorders. Isoflavones are considered to be phytoestrogens because of their ability to bind to estrogen receptors. The literature is extensive on the chemistry, bio-availability, and bio-activity of isoflavones. However, their effects on immune response are yet to be fully understood, but are beginning to be appreciated. We review the role of isoflavones in regulation of the immune response and their potential clinical applications in immune-dysfunction. Special emphasis will be made regarding in vivo studies including humans and animal model systems.
One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) alpha and beta are ligand-dependent transcription factors that are expressed in skin, and an ERbeta agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERbeta does not carry the breast and uterine proliferation liabilities of ERalpha, we decided to explore the possibility of using ERbeta as a target for photoaging. We show that ERbeta-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERbeta-selective compounds also inhibited COX-2. These activities of ERbeta ligands in skin cells correlated with the expression levels of ERbeta and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERbeta-selective compound was observed in wild-type but not in skin cells obtained from ERbeta knockout mice. Finally, we demonstrate that a synthetic ERbeta agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERbeta ligand to regulate multiple pathways underlying the cause of photoaging suggests ERbeta to be a novel therapeutic target for the prevention and treatment of photoaging.
The role of estradiol in the regulation of its cognate receptor in MCF-7 cells was investigated in this study. After treatment with 10(-9) M estradiol, the level of receptor protein was measured using an enzymeimmunoassay. By 6 h, the receptor protein declined by about 60% from a level of approximately 3.6 to 1.2 fmol/micrograms DNA. The level of receptor remained suppressed for 24-48 h. Similar results were obtained with an estrogen receptor (ER) binding assay. The steady state level of ER mRNA was determined by an RNase protection assay. Estrogen treatment resulted in a maximum suppression of mRNA by 6 h. Receptor mRNA remained depressed for 48 h. Transcription run on experiments demonstrated a transient decrease of about 90% in ER transcription after 1 h. By 3-6 h transcription increased approximately 2-fold and remained elevated for at least 48 h. These data suggest that estrogen down-regulates ER mRNA by inhibition of ER gene transcription at early times and by a posttranscriptional effect on receptor mRNA at later times.
Poly(A)+ RNA isolated from the human breast cancer cell line MCF-7 was fractionated by sucrose gradient centrifugation and fractions enriched in estrogen receptor (ER) mRNA were used to prepare randomly primed cDNA libraries in the lambda gt10 and lambda gt11 vectors. Clones corresponding to ER sequence were isolated from both libraries after screening with either ER monoclonal antibodies (lambda gt11) or synthetic oligonucleotide probes designed from two peptide sequences of purified ER (lambda gt10). Five cDNA clones were isolated by antibody screening and five were isolated after screening with synthetic oligonucleotides. The two largest ER cDNA clones, lambda OR3 (1.3 kilobase pairs) and lambda OR8 (2.1 kilobase pairs), isolated by using antibodies and oligonucleotides, respectively, were able to enrich selectively for ER mRNA by hybrid-selection. Furthermore, lambda OR8 contains the DNA sequence expected from the two ER peptides and crosshybridizes with each of the other ER cDNA clones. These results demonstrate that the clones isolated correspond to the ER mRNA sequence. Use of lambda OR8 as a hybridization probe revealed a single poly(A)+ RNA band of approximately equal to 6.2 kilobase pairs in the ER-containing human breast cancer cell lines MCF-7 and T47D. In contrast, no hybridization was seen in the human ER-negative cell line HeLa. The same probe hybridizes to a chicken gene that is expressed in oviduct tissue as a 7.5-kilobase-pair poly(A)+ RNA.
The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 > zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 > genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.
Sex steroid hormones are involved in regulation of skin development and functions as well as in some skin pathological events. To determine the sites of action of estrogens, androgens and progestins, studies have been performed during the recent years to accurately localize receptors for each steroid hormone in human skin. Androgen receptors (AR) have been localized in most keratinocytes in epidermis. In the dermis, AR was detected in about 10% of fibroblasts. In sebaceous glands, AR was observed in both basal cells and sebocytes. In hair follicles, AR expression was restricted to dermal papillar cells. In eccrine sweat glands, only few secretory cells were observed to express AR. Estrogen receptor (ER) alpha was poorly expressing, being restricted to sebocytes. In contrast, ERbeta was found to be highly expressed in the epidermis, sebaceous glands (basal cells and sebocytes) and eccrine sweat glands. In the hair follicle, ERbeta is widely expressed with strong nuclear staining in dermal papilla cells, inner sheath cells, matrix cells and outer sheath cells including the buldge region. Progesterone receptors (PR) staining was found in nuclei of some keratinocytes and in nuclei of basal cells and sebocytes in sebaceous glands. PR nuclear staining was also observed in dermal papilla cells of hair follicles and in eccrine sweat glands. This information on the differential localization of sex steroid receptors in human skin should be of great help for future investigation on the specific role of each steroid on skin and its appendages.
A review of the medical literature concerning the effect of the menopause and its hormonal treatment on the skin.
An extensive Medline and Pubmed internet search utilizing the key words: collagen, elastin, estrogen, hormone replacement therapy, skin and aging.
The literature review demonstrated a wide array of research ranging from basic science work to clinical implications of the effects of the menopause and its treatment on the skin.
Estrogen loss at menopause has a profound influence on skin. Estrogen treatment in postmenopausal women has been repeatedly shown to increase collagen content, dermal thickness and elasticity, and data on the effect of estrogen on skin water content are also promising. Further, physiologic studies on estrogen and wound healing suggest that hormone replacement therapy (HRT) may play a beneficial role in cutaneous injury repair. Results on the effect of HRT on other physiologic characteristics of skin, such as elastin content, sebaceous secretions, wrinkling and blood flow, are discordant. Given the responsiveness of skin to estrogen, the effects of HRT on aging skin require further examination, and careful molecular studies will likely clarify estrogen's effects at the cellular level.
There is mounting evidence that menopause affects some functions of the skin. Hormone replacement therapy (HRT) appears to limit some of the climacteric aspects of cutaneous aging.
In the light of a growing interest in the endocrinological influence of skin, we performed a study evaluating the effects of HRT on skin aging in postmenopausal women.
Forty non-hysterectomized, postmenopausal women were included in this prospective, randomized, double-blind, placebo-controlled study on the influence of oral sequential treatment with a combination of 2 mg 17beta-estradiol/10 mg dydrogesterone (Femoston) for seven 28-day cycles. Skin elasticity, skin surface lipids, skin hydration and skin thickness were measured by non-invasive methods, and both adverse-event profile and clinical-dermatological status were evaluated.
After 7 months of HRT, skin elasticity increased significantly at the right ramus of the mandible, while skin hydration tended to improve significantly at the right upper arm (inner side); skin thickness improved significantly but skin surface lipids did not. Absolute effects did not differ significantly between HRT and placebo patients. A dermatological evaluation was largely consistent with measurement results. Safety and tolerability of HRT were positive.
The results showed improvements in the parameters involved in skin aging in the HRT group as compared to baseline. While skin aging is no indication for systemic hormone supplementation, a positive effect on aging skin can be observed.
In humans, structural and functional changes attributable to aging are more visibly evident in the skin than in any other organ. Estrogens have significant effects on skin physiology and modulate epidermal keratinocytes, dermal fibroblasts and melanocytes, in addition to skin appendages including the hair follicle and the sebaceous gland. Importantly, skin aging can be significantly delayed by the administration of estrogen. This paper reviews the effects of estrogens on skin and the mechanisms by which estrogens can alleviate the changes due to aging that occur in human skin. The relevance of estrogen replacement therapy (HRT) in postmenopausal women and the potential value of selective estrogen receptor modulators (SERMs) as a therapy for diminishing skin aging are also highlighted.
Isoflavones, one main group of phytoestrogens, have antioxidative and photoprotective effects in cellular and mouse studies. The aim of this study is to obtain a more comprehensive understanding of the isoflavone-mediated photoprotection with the pig skin model, a more human-resembling model.
The pig skin was treated with five well-known isoflavone compounds (genistein, equol, daidzein, biochanin A, and formononetin) and one antioxidant combination solution of 15% vitamin C and 1% vitamin E and 0.5% ferulic acid (CEF) daily for 4 days. Skin was irradiated with solar-simulated UV irradiation, 1 to 5 minimal erythema dose (MED) at 1-MED intervals. Evaluation was carried out 24 h later by colorimeter-measured erythema and sunburn cell numbers.
Topical application of 0.5% solutions of three individual phytoestrogens - genistein, daidzein, biochanin A - are better than similar solutions of equol or formononetin in protecting pig skin from solar-simulated ultraviolet (SSUV)-induced photodamage, as measured by sunburn cell formation and/or erythema. However, the protection was less than that provided by a topical combination antioxidant standard containing 15% L-ascorbic acid, 1%alpha-tocopherol, and 0.5% ferulic acid.
Isoflavones provide effective photoprotection and are good candidate ingredients for protection against ultraviolet (UV) photodamage.
Objective:
To evaluate the relation between noncontraceptive estrogen use and skin wrinkling, dryness, and atrophy.
Design:
Cross-sectional analysis of a national probability sample-based cohort study.
Setting:
Multiple community sites throughout the United States.
Participants:
Postmenopausal women (n=3875) aged 40 years and older at baseline.
Measurements:
Skin conditions (wrinkling, dryness, and atrophy) were ascertained using a uniform clinical examination by trained dermatology resident physicians. Self-reported use of estrogen before the baseline examination, sunlight exposure, and smoking history were obtained by standardized interview. Body mass index, a measure of weight in kilograms divided by the square of the height in meters, was evaluated in uniform examination clothing.
Results:
Mean (±SD) age of the participants was 61.6 (±9.0) years and mean (±SD) number of years since menopause was 15.6 (±9.4). Most were white (83.7%), the remainder being African American (15.9%) or another race (0.4%). Atrophy was present in 499 (16.2%), dry skin in 1132 (36.2%), and wrinkled skin in 880 women (28.2%). The prevalence of all 3 skin conditions was lower in African American women compared with white women. Information on hormone use was available for 3403 participants (88%). Among all women, after adjustment for age, body mass index, and sunlight exposure, estrogen use was associated with a statistically significant decrease in the likelihood of senile dry skin (odds ratio, 0.76; 95% confidence interval, 0.60-0.97). The odds of wrinkling were substantially lower in estrogen users, adjusted for age, body mass index, and sun exposure (odds ratio, 0.68; 95% confidence interval, 0.52-0.89) and additionally for smoking (odds ratio, 0.67; 95% confidence interval, 0.44-1.01). In multivariable models, estrogen use was not associated with skin atrophy.
Conclusion:
These results strongly suggest that estrogen use prevents dry skin and skin wrinkling, thus extending the potential benefits of postmenopausal estrogen therapy to include protection against selected ageand menopause-associated dermatologic conditions.Arch Dermatol. 1997;133:339-342
Collagen atrophy is a major factor in skin ageing. A strong correlation exists between skin collagen loss and oestrogen deficiency caused by the menopause. Skin ageing is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Oestrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations about postmenopausal oestrogen use and its role in preventing skin ageing.
The aim of this work was to compare the effects of estradiol and genistein treatment on hyaluronic acid (HA) concentration in postmenopausal facial skin.
In this study, 30 postmenopausal women were evaluated in a prospective, randomized, double-blind trial. The volunteers were postmenopausal women treated in the Gynecology Department of the Federal University of São Paulo. The participants were divided into two groups: group E, treated with 0.01% 17β-estradiol gel (n = 15), and group G, treated with 4% genistein gel (isoflavones, n = 15). The treatment lasted for 24 consecutive weeks. Preauricular skin biopsies were performed for each participant at baseline (E1 and G1) and after treatment (E2 and G2) to evaluate HA concentration in tissue. The materials were processed using immunohistochemical and biochemical methods.
After 24 weeks of treatment, HA concentration increased in both groups, but the effect was greater for estradiol treatment than for genistein treatment.
Our data suggest that both treatments may enhance HA concentration in postmenopausal skin but that estrogen produces results that are greater than those produced by isoflavones.
The aging global population continues to drive increasing demand for cosmaceuticals and cosmetic surgery among older men and women. Since the discovery in the 1990s that estrogen receptors are present in skin cells and decline in number from the onset of menopause in women, researchers have explored a number of ways in which estrogen can improve skin condition. Skin is estrogen responsive, and several studies now exist to support the antiaging properties of estrogen replacement therapies in postmenopausal women. Both systemic and topical estrogens appear to have positive effects on hormonal aging, increasing skin collagen content, thickness, elasticity and hydration. Estrogen therapies may also improve wound healing and reduce the incidence of wound complications. This review explores the potential for targeted estrogen replacement as a therapeutic option for long-term skin management in postmenopausal women.
Intrinsic skin aging represents the biological clock of the skin cells per se and reflects the reduction processes that are common in internal organs. The reduced secretion of the pituitary, adrenal glands, and the gonads contributes to characteristic aging-associated body and skin phenotypes as well as behavior patterns. Our knowledge of whether there is a direct or indirect connection between hormonal deficiency and skin aging still remains limited. In females, serum levels of 17β-estradiol, dehydroepiandrosterone, progesterone, growth hormone (GH), and its downstream hormone insulin-like growth factor I (IGF-I) are significantly decreased with increasing age. In males, serum levels of GH and IGF-I decrease significantly, whereas it can decrease in late age in a part of the population. Hormones have been shown to influence skin morphology and functions, skin permeability, wound healing, sebaceous lipogenesis, and the metabolism of skin cells. Prevention of skin aging by estrogen/progesterone replacement therapy is effective if administered early after menopause and influences intrinsically aged skin only. Vitamin D substitution and antioxidant treatment may also be beneficial. Replacement therapy with androgens, GH, IGF-I, progesterone, melatonin, cortisol, and thyroid hormones still remains controversial.
Oestrogen (17β estradiol) and the dietary antioxidants resveratrol, genistein and S-equol, an isoflavone produced from the gut biotransformation of soy daidzein, are effective agents to reduce ageing in skin. It is widely held that these antioxidants scavenge free radicals to prevent skin damage. However, the evidence to date suggests that the primary mechanism of action of these antioxidants is to activate oestrogen receptor β (ERβ), which in turn enhances the expression of antioxidant enzymes and inhibits the expression of snail, a transcription factor that regulates keratinocyte cell proliferation and migration. Based on their selectivity, ERβ agents provide a treatment option for ageing skin without the potential safety issues associated with oestrogen therapy.
Aging of the skin is associated with skin thinning, atrophy, dryness, wrinkling, and delayed wound healing. These undesirable aging effects are exacerbated by declining estrogen levels in postmenopausal women. With the rise in interest in long-term postmenopausal skin management, studies on the restorative benefits that estrogen may have on aged skin have expanded. Systemic estrogen replacement therapy (ERT) has been shown to improve some aspects of skin. Estrogen restores skin thickness by increasing collagen synthesis while limiting excessive collagen degradation. Wrinkling is improved following estrogen treatment since estrogen enhances the morphology and synthesis of elastic fibers, collagen type III, and hyaluronic acids. Dryness is also alleviated through increased water-holding capacity, increased sebum production, and improved barrier function of the skin. Furthermore, estrogen modulates local inflammation, granulation, re-epithelialization, and possibly wound contraction, which collectively accelerates wound healing at the expense of forming lower quality scars. Despite its promises, long-term ERT has been associated with harmful systemic effects. In the search for safe and effective alternatives with more focused effects on the skin, topical estrogens, phytoestrogens, and tissue-specific drugs called selective estrogen receptor modulators (SERMs) have been explored. We discuss the promises and challenges of utilizing topical estrogens, SERMs, and phytoestrogens in postmenopausal skin management.
Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun-exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies.
To asses the menopause related symptoms and to determine the impact of these symptoms on the quality of life of menopausal women.
It was a cross sectional hospital based survey conducted at the department of Obstetrics and Gynecology Isra University Hyderabad Sindh Pakistan from November 2007 to August 2008. Two hundred two women of age 40-60 years, who presented in out patient department were included. Women with induced menopause, receiving hormonal treatment, having medical problems like thyroid disorders, diabetes mellitus and hypertension and those who refused to participate were not included. Menopause specific quality of life questionnaire (MENQOL) was used to assess the frequency and severity of symptoms. Mann-Whitney U test and Pearson Co-efficient of correlation was used for statistical analysis. P value < 0.05 was considered significant.
Mean age of women was 52.17 +/- 6.019 years. Mean length of time since menopause was 8.39 +/- 6.0 years. Most prevalent symptom within study subjects was body ache 165 (81.7%). Frequencies of some classical symptoms were 134 (66.3%) reported "hot flushes", 139 (68.8%) and 134 (66.3%) reported "lack of energy" and decrease in "physical strengths" respectively. The less frequently reported symptom was increase in facial hair 20 (9.9%). Scores of Physical domain were significantly more in postmenopausal (PM) group P < 0.002 while the scores of psychological domain were significantly high in menopause transition (MT) group P < 0.003.
Menopause related symptoms had negative affect on the quality of life of postmenopausal women.
Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor
alpha (ERα) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation
of transcription by estrogen-bound ERα has been studied in detail, as has antagonist-induced repression, such as that which
occurs by tamoxifen. How estrogen-bound ERα represses gene transcription remains unclear. In this report, we identify a new
mechanism of estrogen-induced transcriptional repression by using the ERα gene, ESR1. Upon estrogen treatment, ERα is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at
both ERα-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications
occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression
of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ERα is identified. These data support a model of repression
wherein actions of ERα and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and
ultimately decrease gene expression.
The aim of this study was to evaluate the effects of estrogen and isoflavones on postmenopausal skin morphological parameters.
A randomized, double-blind, estrogen-controlled trial was performed on postmenopausal women treated in the Gynecology Department of the Federal University of São Paulo. This study was designed to analyze the effects of topical administration of estradiol and isoflavones on facial skin for 24 weeks. The participants were divided into two groups: G1-17-betaestradiol 0.01% (n=18) and G2-isoflavones 40% (genistein 4%, n=18). Skin biopsies were performed on each patient before and after the treatment. The skin samples were processed for histological analysis, stained with haematoxylin and eosin, and examined using light microscopy.
After 24 weeks of treatment, the estradiol group had a significant increase in skin parameters analyzed compared to the isoflavone group and to the baseline measurements: epidermal thickness (a 75% increase in the estrogen group and 20% in the isoflavone group), number of dermal papillae (a rise of 125% with estrogen, no significant gain with isoflavones), fibroblasts (a 123% accretion with estradiol, no significant gain with isoflavones), and vessels (a 77% increase with estrogen and 36% with isoflavones).
Our data suggest that estrogens may have a stronger effect on histomorphometrical parameters than isoflavones.
To evaluate the effectiveness of topical estradiol in stimulating collagen I and III production in naturally aged and photoaged human skin of postmenopausal women and age-matched men.
Vehicle-controlled treatment followed by biochemical and immunohistochemical analyses of skin biopsy specimens.
Academic referral center.
Seventy healthy volunteers (40 postmenopausal women with a mean age of 75 years, and 30 men with a mean age of 75 years) with photodamaged skin. Interventions Topical application of estradiol, 0.01%, 0.1%, 1%, or 2.5% or vehicle on aged or photoaged skin, with biopsy specimens taken after last treatment.
De novo synthesis of collagen by quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay.
Topical estradiol increased procollagen I and III messenger RNA and collagen I protein levels in sun-protected aged hip skin in postmenopausal women and, to a lesser extent, in age-matched men. Surprisingly, no significant changes in production were observed in women or men after 2-week estradiol treatment of photoaged forearm or face skin, despite similar expression of estrogen receptors (ER-alpha, ER-beta, and GPR30) in aged and photoaged skin. Estradiol treatment induced the estrogen-responsive gene GREB1, indicating that penetration of topical estradiol and genomic response to estrogen were similar in the 3 anatomic sites.
Two-week topical estradiol treatment stimulates collagen production in sun-protected hip skin, but not in photoaged forearm or face skin, in postmenopausal women and aged-matched men. These findings suggest that menopause-associated estrogen decline is involved in reduced collagen production in sun-protected skin. Interestingly, alterations induced by long-term sun exposure hinder the ability of topical 2-week estradiol to stimulate collagen production in aged skin.
clinicaltrials.gov Identifier: NCT00113100.
Skin signs and symptoms were examined in 46 menopausal women prior to estrogen replacement therapy. Several symptoms such as pruritus, bruising, dryness and thinning were seen more frequently in sun-exposed skin emphasizing the contribution of photoaging. At the end of a 6-mth treatment period, no significant difference was observed in the prevalence or severity of the cutaneous signs and symptoms when patients receiving transdermal 17 beta-estradiol (Estraderm) were compared with controls (the only exception was cutaneous flushing). Elastic fibers from sun-protected (buttock) skin of menopausal women were studied by light and electron microscopy. In 3 women (ages 30-37) with a history of premature menopause, the elastic fibers had several degenerative changes including coalescence of cystic spaces into lacunae, peripheral fragmentation, granular degeneration and splitting of the fibers into strands. Similar age-related ultrastructural changes are normally found in individuals that are at least 20 yrs older than these patients. These findings are suggestive of a relationship between premature aging of the dermal elastic fibers and estrogen deprivation.
The skin collagen content, skin thickness, metacarpal index, and forearm bone mineral content in postmenopausal women showed a similar decline of between 1-2% per year after the menopause. All four parameters showed a decline that was significant when compared with the years from the menopause. Significant correlations between all four parameters suggest that a similar pathology causes the decrease in bone mass and skin thickness--a decline in the connective tissue element that is common to both bone and skin.
The effect of local oestriol treatment on the abdominal skin was studied in 14 postmenopausal women. Six control patients received a similar ointment without oestriol. The duration of the treatment in all cases was three weeks. The elastic fibers in the papillary dermis were thickened, better orientated and slightly increased in number in half of these patients but in none of the control patients. The epidermal thickness was slightly increased in four of the patients treated with oestriol. No significant changes were observed in the epidermal cell size, mitotic activity, dermal vascularization or inflammatory infiltrate between the specimens taken before and after the treatment or between the treatment groups.
In summary, the aging process in skin has at least two major manifestations: elastic fiber abnormalities involving degradation and assembly, and microvascular wall alterations of widening and atrophy depending upon the functional state of the veil cell. The abnormalities of the elastic fiber network most likely correlate with the increasing cutaneous laxity associated with aging. The microvascular abnormalities are not easily related to any specific clinical feature of aging skin. The finding of identical abnormalities in the skin of juvenile diabetics strengthens this hypothesis, as well as suggesting that these alterations are accelerated in diabetic patients. Diabetic skin might be another model system for studying cutaneous aging.
We examined cytological vaginal smears of 17 women before and after three months of dermal estrogen (1 g of 0.01% estradiol ointment or 0.3% estriol ointment once daily), applied to the face for dermatological indications. The mean age was 57.1 +/- 7.6 years (range from 46 to 66). Seven women had estrogenic smears (more than 10% superficial cells) before therapy. Nine women were treated with 0.01% estradiol ointment and 8 were treated with 0.3% estriol ointment. Both groups had gynecological examinations including cervical and vaginal smears before and after treatment and also monthly measurements of serum follicle-stimulating hormone, prolactin and estradiol levels. Serum hormone levels and the appearance of vaginal smears showed no significant change during treatment.
The coincidence of climacteric symptoms and the beginning of skin aging suggests that estrogen deficiency may be a common and important factor in the perimenopausal woman. Often hormones have been considered important in endogenous aging of the skin, but their role has not been clearly defined. Therefore, we investigated, whether topical treatment of the skin with estrogen could reverse some of the changes in the aging skin.
The effects of 0.01% estradiol and 0.3% estriol compounds were compared in 59 preclimacteric women with skim aging symptoms. Monthly determinations of estrodiol (E2), follicle-stimulating hormone (FSH), and prolactin (PRL) were done and the monthly clinical monitoring was supplemented by measurements of skin hydration by corneometry and profilometry. In 10 patients, skin biopsies were taken for immunohistochemical determination of collagen types I and III.
After treatment for 6 months, elasticity and firmness of the skin had markedly improved and the wrinkle depth and pore sizes had decreased by 61 to 100% in both groups. Furthermore, skin moisture had increased and the measurement of wrinkles using skin profilometry, revealed significant, or even highly significant, decreases of wrinkle depth in the estradiol and the estriol groups, respectively. On immunohistochemistry, significant increases of Type III collagen labeling were combined with increased numbers of collagen fibers at the end of the treatment period. As to hormone levels, only those of PRL had increased significantly and no systemic hormonal side effects were noted.
To determine the relationship between skin collagen IV and basement membrane changes during aging, a total of 35 women who had been admitted for surgery, were studied.
Subjects were arranged into six age-groups (from 35 to 60 years). Skin biopsies were performed in all patients and the samples were taken from a site 6 cm above the pubic symphysis. The collagen IV content and the epithelial basement membrane were analyzed by using immunohistochemical, transmission electron microscopy and computer-assisted image analysis methods. The skin collagen IV content was measured by an image analysis program and expressed in arbitrary units of integrate optical density, and, the basement membrane thickness was expressed in nanometers.
Type IV collagen content decreased with age after 35 years (r = -0.9561). The epithelial basement membrane thickness increased significantly with age (r = 0.98192; P < 0.01) and there is an inverse correlation between these two parameters (r = -0.990502).
Although type IV collagen is a basement membrane component and declines with aging, the total thickness of this membrane increases, which suggests a reduction in tissue turnover.
Human estrogen receptor beta (hER beta) cDNA that encodes the full-length amino acid sequence has been isolated from testis poly(A)+ RNA with the combination of cDNA screening and reverse transcription-PCR. It is composed of a 1590-bp open reading frame and a segment of the 5'- and 3'-untranslated region (UTR) and encodes an additional 53 amino acids in the N-terminal region compared with the previously reported one. Protein interaction between ER alpha and ER beta was demonstrated in vitro by GST pull-down assay and in vivo by immunoprecipitation. Thus, this study indicates that ER alpha and ER beta can interact in vivo, cross-signaling each other.
Since the early 1940s, scientists have examined the effect of soy protein on blood cholesterol concentrations. Although studies in animals have suggested that soy protein lowers blood cholesterol concentrations, similar studies in humans have yielded less consistent results. The presence or absence of the soybean isoflavone fraction may be a confounding factor. This fraction, consisting primarily of genistein, daidzein and glycetein, has been shown to have a hypocholesterolemic effect in animals and humans. Potential mechanisms by which soy protein and/or isoflavones induce lowering of blood cholesterol concentrations include thyroid status, bile acid balance and the estrogenic effects of genistein and daidzein. Some studies have suggested that isoflavones exhibit antioxidant properties and have favorable effects on arterial compliance. In addition to the aforementioned potential beneficial effects, the increased consumption of products containing soy protein may displace foods relatively high in saturated fat and cholesterol from the diet and hence have an indirect blood cholesterol-lowering effect.
To investigate the effects of topically applied 17beta-estradiol on the expression of extracellular matrix proteins in aged human skin, 17beta-estradiol (0.01%) and its vehicle (70% propylene glycol, 30% ethanol) were applied to aged (68-82 y, eight females and five males) human buttock skin under occlusion for 2 wk (three times per week). Topical 17beta-estradiol was found to increase the expression of type 1 procollagen mRNA and protein significantly in human aged skin in vivo. In addition, metalloproteinase (MMP-1 protein levels were reduced by topical 17beta-estradiol. The expressions of TGF-beta1, TGF-beta type II receptor, and Sma and Mad related (Smad)3 were increased by topical 17 beta-estradiol in aged human skin, and TGF-beta1 neutralizing antibody inhibited 17beta-estradiol-induced procollagen synthesis in cultured fibroblasts. We also found that the expressions of tropoelastin and fibrillin-1 mRNA and protein, and elastic fibers in aged skin were also increased by topical 17beta-estradiol. Topical 17beta-estradiol also increased keratinocyte proliferation and the epidermal thickness in aged human skin. We also observed the same effects of topical 17beta-estradiol in young skin. In conclusion, our results suggest that topical 17beta-estradiol treatment may improve the cutaneous function of aged human skin by improving the connective tissue and increasing epidermal thickness.
- J L Bolognia
- I M Braverman
- M E Rousseau
- P M Sarrel
J. L. Bolognia, I. M. Braverman, M. E. Rousseau,
and P. M. Sarrel, Skin changes in menopause,
Maturitas, 11, 295 (1989).
Repression of ESR1 through actions of estrogen receptor α and Sin3A at the proximal promoter
- S J Ellison-Zelski
- N M Solodin
- E T Alarid
S. J. Ellison-Zelski, N. M. Solodin, and E. T. Alarid,
Repression of ESR1 through actions of estrogen receptor α and Sin3A at the proximal promoter, Mol.
Cell. Biol., 29, 4949 (2009).
- M P Brincat
- Y M Baron
- R Galea
M. P. Brincat, Y. M. Baron, and R. Galea, Estrogens
and the skin, Climacteric, 8, 110 (2005).