The life expectancy of women has increased significantly in the last century. In the
United States, it was approximately 50 years in 1900 and currently exceeds 80 years,
according to the World Health Organization1. In Brazil, according to the IBGE (Brazilian Institute of Geography and Statistics,
in portuguese: Instituto Brasileiro de Geografia e Estatística), in 1940, it was 48.3 years, and in 2015 it reached 79.1 years2. Thus, today it is expected that women spend more than a third of their lives after
menopause, which leads to greater concern about health care in this period3.
Skin quality deteriorates with age due to chronological aging, photoaging, environmental
factors, and hormone deficiencies. Menopause is a milestone in a woman’s life, accompanied
by a significant drop in hormone levels. This change causes numerous climacteric symptoms,
including the accelerated decline of skin conditions. The drop in estrogen levels
that occurs during this period plays an important role in skin atrophy, in the reduction
of collagen and water content, in the reduction of sebaceous secretions, in the loss
of elasticity and wrinkling of the skin, and, in addition, in the impairment of wound
Studies show evidence that changes in estrogen levels are associated with the perception
of aging. According to Lephart, in his study, a positive correspondence was demonstrated
between estrogen levels and perceived age, facial attractiveness, skin color, and
Consequently, careful study of the molecular effects of estrogen on the skin and the
corresponding cutaneous manifestations is important.
The important role of estrogen in skin integrity was demonstrated with the discovery
of estrogen receptors in dermal fibroblasts and epidermal keratinocytes4, 6, 7, 8. It acts through two distinct mechanisms: the classic pathway, with estrogen receptors
ERa and ERb, which involves the nuclear location of the hormone-receptor complex,
by which the expression of target genes is altered, and the non-classical pathway,
which initiates a rapid cascade of intracellular signaling by coupling the hormone
to estrogen receptors on the cell membrane, including the G-protein coupled estradiol
receptor (GPER or GPR30). Thus, estrogen can exert its physiological effects through
a combination of genomic and non-genomic pathways9.
Estrogens generally improve collagen content and quality and increase dermal thickness
and vascularity. In addition, they improve the migration of keratinocytes and, consequently,
accelerate the wound healing process7.
Studies have shown that 17 b-estradiol and genistein can combat skin aging, protecting
fibroblasts and keratinocytes against peroxidation. They act by modulating the oxidant/antioxidant
system and the mitochondrial membrane potential through mechanisms related to estrogen
receptors (classical and non-classical) and to the activation of kinases6, 8, 10.
The topical use of estrogens and phytoestrogens has demonstrated beneficial effects
on preventing and repairing skin aging in postmenopausal women11, 12, 13, 14, 15, 16. The importance of estrogen in maintaining human skin homeostasis is evidenced by
the sudden acceleration of skin aging observed in women during the climacteric9, 11.
Phytoestrogens represent promising alternatives for treating skin aging, especially
genistein, which has anti-photocarcinogenic and anti-photoaging properties by modulating
the oxidant/antioxidant balance8. Phytoestrogens are substances plants produce with structural and functional properties
similar to estrogens. Thus, they bind directly to estrogen receptors, exerting agonist
and antagonist effects. Isoflavones have been shown to promote beneficial effects
on aging skin regarding photoprotection, elasticity, hydration, and wrinkle prevention9.
In recent years, much research has been carried out to elucidate the effects of topical
estrogens and phytoestrogens, which would have a more localized action on the skin
without the side effects of systemic hormone replacement. Studies have concluded that
phytoestrogens have comparable efficacy to estrogen in skin aging. In addition, because
they are plant-derived compounds with fewer possible side effects, they could be safer
for topical use17.
Thus, the localized use of these hormones in small areas, such as the face, neck,
and decollete, is a safe and effective alternative for treating the skin of perimenopausal
To review national and international scientific production through a narrative review
of the literature to assess the role of topical phytoestrogens in human skin and their
effect on skin rejuvenation.
This is a narrative literature review of articles in journals in Portuguese and English
published from 1996 to 2021. Bibliographical research was carried out from January
to March 2021 through the search sources constituted by electronic resources in the
following databases data: Latin American and Caribbean Literature on Health Sciences
(LILACS), Health Information from the National Library of Medicine (Medline), Web
of Science, Scopus and the Scientific Electronic Library Online (SciELO).
The descriptors (DeCS) used were: Fitoestrógenos/Phytoestrogens, Genisteína/Genistein, Estrogênios/Estrogens, Envelhecimento da pele/Skin aging, Colágeno/Collagen, Administracao tópica/Topical Administration.
Additionally, a detailed manual search of the references of selected articles was
performed to find studies not identified in the online search.
After identifying the articles, in the search mentioned above sources, the following
selection criteria were used (Chart 1).
Chart 1 - Article selection criteria.
• Clinical studies in perimenopausal women treated with topical estrogen or phytoestrogen
• Literature reviews on the effects of topical estrogen and phytoestrogen on human
skin and skin aging
• Clinical studies with histological sections and cultures of human cells and the
effects of estrogens and phytoestrogens in vitro
• Clinical studies evaluating the effects of estrogens and phytoestrogens on the skin
of animals and the molecular mechanisms of action of these hormones
• Clinical Studies with systemic hormone replacement
• Case reports
• Duplicate articles
• Articles with conflict of interest
Chart 1 - Article selection criteria.
In all, 15 clinical studies and 7 literature reviews were selected.
In women, chronological aging is accompanied by a significant drop in hormone levels
during climacteric and menopause. These changes lead to numerous symptoms, including
the accelerated decline of skin conditions. With the increase in women’s life expectancy
and, consequently, the interest in skin care after menopause, studies on the beneficial
effects of estrogens and phytoestrogens on skin in aging have increased a lot.
Long-term systemic hormone replacement therapy has been associated with unwanted systemic
effects, according to the Women’s Health Initiative (WHI) Study, Heart and Estrogen
Replacement Study (HERS), and Million Women Study18, 19, 20. Thus, in the search for safe and effective alternatives, the more localized effects
of topical estrogens and phytoestrogens on the skin have been explored.
Phytoestrogens are substances plants produce with structural and functional properties
similar to estrogens. There are three main classes: isoflavones, lignans, and coumestans21. Among these, isoflavones, especially genistein, are the best studied. These bind
directly to estrogen receptors, exerting both agonist and antagonist effects. Numerous
studies have shown that isoflavones promote beneficial effects on aging skin regarding
photoprotection, elasticity, hydration, and wrinkle prevention11, 22.
Bayerl & Keil12, in a European multicenter controlled clinical study, in 2002, examined the effect
of a cosmetic cream preparation, including isoflavone, in 234 women with a maximum
age of 65 years, at least three years after menopause, with no replacement therapy
hormone (HRT) or other substances that affect the skin’s aging process. The duration
of therapy was 12 weeks. The isoflavone cream was applied twice daily (in the morning
at a concentration of 0.0075% and night at 0.015%) on the face, neck, and one arm.
The other arm was not treated and served as a control.
Skin hydration and texture significantly improved in treated areas by 32.9% and 22%,
respectively, compared to untreated areas. Facial wrinkles were significantly reduced
by 22%, and skin sagging was significantly reduced by 24%12.
Genistein has a molecular structure very similar to that of estradiol, has significant
effects on the skin due to its ability to bind to estrogen receptors, and has been
shown to provide protective effects against photoaging and photocarcinogenesis in
human and animal skin when applied topically23, 24, 25.
In a double-blind, randomized study by Moraes et al.14, in 2009, 4% genistein gel was applied topically to the facial skin of postmenopausal
women for 24 weeks, with improvement in dermal vascularization and an increase in
Patriarca et al.15, in a prospective, randomized, double-blind study, in 2013, with 30 postmenopausal
women, demonstrated an increase in the concentration of hyaluronic acid and fibroblasts
in the dermis after topical treatment for 24 weeks with 4% genistein and 0.01% 17β-estradiol.
In a randomized, double-blind study, in 2017, with 30 patients aged between 45 and
55 years, Silva et al.16 compared the effects of topical estrogen and topical genistein on the skin collagen
of postmenopausal women. Patients were divided into three groups: topical estradiol,
topical genistein, and control. A statistically significant increase in collagen type
I and III was observed in both estradiol and genistein groups. The possibility of
systemic absorption of topical estrogen was also a variable studied, with vaginal
smears and transvaginal ultrasound being performed to measure the thickness of the
endometrium before and after treatment.
In addition, serum estradiol dosage was performed before and 24 weeks after treatment.
Initially, all selected women had vaginal and endometrial atrophy, with serum estradiol
levels below 20pg/ml. None of these parameters changed after treatment. Based on these
results, it can be inferred that topical therapy with estrogen and genistein does
not produce significant systemic side effects16.
Desmawati & Sulastri26, in 2019, carried out a review study on phytoestrogens and their effects. It has
been described that phytoestrogens are structurally similar compounds to 17β-estradiol.
Among phytoestrogens, isoflavones are the most studied and are found in soy and other
legumes. The amount of isoflavones needed to produce health effects is 40 to 70 mg
daily. The main phytoestrogens, in the form of isoflavones, are genistein, daidzein,
glycitein, formononetin, and biochanin.
The authors described that phytoestrogens could act with an anti-aging effect on the
skin through estrogen receptors. They lead to increased hyaluronic acid, collagen,
and extracellular protein matrix production. In addition, phytoestrogens can also
increase vascularity and cell proliferation in the skin and prevent oxidative stress
and apoptosis. Studies analyzed by the authors showed a reduction in cell death induced
by ultraviolet radiation in cultured keratinocytes, an improvement in skin elasticity
and thickness, and an increase in the production of procollagen type 126.
Rzepecki et al.27, in 2019, carried out a review study aiming to provide an overview of the role of
estrogen in the skin and the changes associated with its deficiency. Specifically,
clinical studies using topical estrogens and topical isoflavones were analyzed. Improvement
was observed in several parameters analyzed in the studies, both with estrogens and
isoflavones. There was an increase in skin elasticity, epidermal thickness, hyaluronic
acid concentration, and collagen concentration. Improvements in facial wrinkles, skin
texture, hydration, sebum production, and wound healing have been observed. There
were no significant systemic changes. The effects described were more noticeable in
the estrogen-treated groups.
However, studies have shown that topically applied phytoestrogens have comparable
efficacy to estrogens. In addition, some isoflavones (especially genistein) stand
out for having a high affinity for ER-β (found more frequently in the skin, bones,
and cardiovascular system) and low affinity for ER-α (more often found in the uterus
and boobs). Thus, due to their ability to be tissue-selective, isoflavones are also
considered selective estrogen receptor modulators (SERMs/SERMs)27.
Therefore, although larger, well-controlled studies are needed, isoflavones are potential
candidates for treating the skin without the negative aspects of systemic estrogen.
Topical estrogens have low systemic absorption and thus low associated risks; however,
genistein is believed to pose an even lower risk due to receptor selectivity. At the
end of the study, the authors concluded that the effects of estrogen deficiency on
the skin are an important endogenous cause of skin aging in women. However, treatment
strategies that aim to act on the underlying hormonal deficiency and not on the resulting
symptoms are limited27.
Liu et al.17, in a narrative review of the literature, in 2020, evaluated the effects of phytoestrogens
on human skin and the mechanisms by which they can alleviate the signs of aging. The
authors described that phytoestrogens could increase collagen and water content in
the skin and protect against oxidative stress. Thus, they can significantly delay
skin aging. The authors discussed the topical application of both estrogen and phytoestrogens.
Both are possible; however, concerning estrogen, they deemed necessary a qualified
specialist doctor who could accompany and monitor the concentration and areas of application,
avoiding any adverse effects.
As for phytoestrogens, they considered them safer because they are compounds derived
from plants with fewer side effects. Finally, this review demonstrates that phytoestrogens
have comparable efficacy to estrogen concerning skin aging. Thus, in recent years,
they have become an important research point in the fight against skin aging17.
Lephart & Naftolin28 did a recent review in 2021 on menopause, its effects on the skin, and innovations
in cosmeceuticals for estrogen-deficient skin. The authors reported that this estrogen-
deficient condition dramatically reduces skin health and well-being, negatively impacting
dermal and homeostatic cellular mechanisms and other important biological functions.
Changes include loss of collagen, elastin, fibroblast function, and vascularity. In
addition, cellular and extracellular degradation occurs, leading to skin dehydration,
wrinkling, atrophy, impaired wound healing, and barrier function. Such factors lead
to a decrease in attractiveness and psychological health, with an increase in the
perception of aging.
The authors report that based on their studies, topical estrogen or phytoestrogen
can reverse these changes. Finally, the authors emphasize the need for a more concentrated
local administration of hormones or innovative cosmeceutical agents, such as selective
estrogen receptor modulators (SERMs/SERMs), including phytoestrogens are promising
actives, for skin care products, especially when it comes to estrogen-deficient skin28.
This study also reported that the plant kingdom is one of the greatest sources of
new cosmeceutical ingredients. Plants are rich in antioxidants as they need to survive
continuous exposure to ultraviolet radiation. The botanicals are considered safe and
meet Food and Drug Administration (FDA) criteria for substances that can be placed
in over-the-counter topical formulations. Thus, many studies have examined phytochemicals
of the polyphenolic class, also known as phytoestrogens, which act as SERMs28.
The drop in serum estrogen levels in the climacteric and menopause is an important
contributor to the decline in skin functions. In turn, hormone replacement with estrogens
or phytoestrogens favorably influences the quality of the skin and its functions in
several aspects, promoting anti-aging action due to its ability to prevent the decrease
in collagen concentration, restore skin elasticity and increase hydration of the skin,
in addition to its important role in improving wound healing. However, despite the
numerous positive effects of estrogen action on the skin, systemic hormone replacement
should not be considered solely to combat skin aging.
On the other hand, studies show that topical treatment with phytoestrogens, especially
genistein, improves skin quality and does not significantly increase the systemic
dosage of these hormones. Thus, topical phytoestrogenic compounds represent a new,
promising, and safe therapeutic approach for skin aging in perimenopausal women.
1. Universidade Federal de São Paulo, Departamento de Cirurgia Plástica, São Paulo,
S P, Brazil.
Corresponding author: Júnia Lira Carneiro Rua Denver 83/601, Santa Lúcia, Belo Horizonte, MG, Brazil. Zip code: 30360-630 E-mail: