Bioactives for Estrogen-Deficient Skin: Topical and Oral Supplement Clinical Studies. A Narrative Review

Abstract

Bioactive compound applications by topical or oral administration have gained increased utilization/awareness in providing health benefits particularly due to changes in hormone levels and aging, especially in women with the decline and loss of estrogens. This narrative review focuses on the bioactive compounds such as the phytoestrogens that have estrogenic properties for improving skin health. Notably, phytoestrogens bind and/or activate estrogen beta receptors, which are abundant in skin layers to improve dermal health. This review presents: (a) skin characteristics with aging in women, (b) changes in hormone levels with aging in women (especially with estrogen deficiency), (c) the characteristics of phytoestrogens and other bioactive compounds, (d) topical and oral clinical studies of bioactive compounds (phytoestrogens) as antiaging treatment(s) for estrogen-deficient skin (during peri- and postmenopause), and (e) the advantages of treating the skin from the outside to inside by traditional topical therapies and treating the skin from the inside to the outside by nutraceutical supplementation, which represents a relatively new innovation of increasing popularity. While this is a growing area of research with promising results, more investigations are needed to understand the mechanism(s) of how combination ingredient formulations work to improve skin health and slow down the advancement of the aging process.

Graphical Abstract

Key Summary Points

Why carry out this review?

Antiaging topical and oral applications include bioactive compounds that have gained increased utilization/awareness in recent years in providing health benefits particularly due to changes in hormone levels and aging especially in women with the decline and loss of estrogen.

What was the focus of this review?

This narrative review focuses on bioactive compounds with estrogenic properties such as the phytoestrogens (e.g., daidzein, genistein, equol, and resveratrol) that bind and/or active estrogen receptors, which are abundant in skin for improving skin health by delaying the visible signs of dermal aging.

What was learned from this review?

This review presents skin aging in women, the decline in hormone levels (especially 17β-estradiol levels) with aging, the benefits of phytoestrogens and other bioactive compounds by reviewing topical and oral clinical studies using these active ingredients as antiaging treatment(s) for estrogen-deficient skin during peri- and postmenopause and covers the advantages of treating the skin from the outside to the inside by traditional topical therapies and also treating the skin from the inside by nutraceutical supplementation to improve skin health and slow down dermal aging.

Digital Features

This article is published with digital features, including a graphical abstract, to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.28742753.

Introduction

Bioactive is an alternative term for biologically active or a bioactive compound of any substance having biological activity directly influencing a living organism [1]. In general, bioactive compound applications by topical or oral administration have gained increased utilization/awareness in providing health benefits via functional foods, nutraceuticals, and other therapies as preventive treatment(s) for various disorders/diseases [2]. Particularly, bioactive compounds are used in a wide range of remedies to ameliorate age-related conditions due to changes in hormone levels [3]. Notably, this is the case with skin aging due to the loss of estrogen with aging, where estrogen-deficient skin is one of the most conspicuous visual markers, especially in the facial, neck, hand, and arm regions of women [4]. However, since there are numerous bioactive compounds such as vitamins, minerals, fatty acids, etc., not all bioactive compounds have estrogenic action(s) associated with their chemical structure. For example, although vitamins and minerals, etc. may enhance skin attributes, they do not have estrogenic characteristics [5, 6]. The main element to be considered is the estrogenic hormonal actions of bioactive compounds such as the polyphenols and/or the phytoestrogens, which fit this attribute owing to their ability to bind and/or active estrogen receptors in skin [7]. In fact, most phytoestrogens act as selective estrogen receptor modulators (SERMs) that bind specifically to estrogen receptor beta (ERβ) found in abundance in the skin and scalp [7, 8]. This is validated by the fact that phytoestrogens have been shown to enhance skin health during the aging process [4, 7] owing to their antioxidant, anti-inflammatory, and other positive dermal actions [7, 8]. To address this point, both ERα and ERβ can meditate anti-inflammatory effects. However, ERβ is often considered a more desirable therapeutic target due to its potential to exert anti-inflammatory actions without the growth-promoting effects on the uterus and mammary gland that occurs with ERα. More importantly as stated above, the skin expresses predominately ERβ in the epidermis and dermis, which has been reported in reviews published elsewhere [4, 7–9].

Thus, the aim of this narrative review is to present in brief: (a) skin characteristics with aging in women, (b) changes in hormone levels with aging in women (especially with estrogen deficiency), (c) define the characteristics of phytoestrogens and other bioactive compounds, and (d) topical and oral applications of bioactive compounds (phytoestrogens) as antiaging treatment(s) for estrogen-deficient skin (during menopause). This narrative overview was accomplished by identifying previous journal articles and reviews (with emphasis over the past 5 to 10 years) using the keywords estrogen-deficient skin and/or menopause plus bioactives, phytochemicals, polyphenols, soy, isoflavones, equol, stilbean, resveratrol, coumarins, daidzein, genistein, lignans, phenolic acids and/or using different keyword combinations (retrieved from October 24 to November 10, 2024). A total of 21 articles were identified (see below using selection criteria). The following databases were utilized: PubMed maintained by the US National Library of Medicine at the National Institutes of Health; Science Direct and Scopus by Elsevier and from Google Scholar. Also, background references (where appropriate) included the keywords estrogen, progesterone, androstenedione, testosterone, and follicle stimulating hormone, aging, menopause, women, skin aging, microbiome, phytoestrogens, phytochemicals, polyphenols, and/or combinations (without a year-limit range for searching the background topics). This overview is based on previously conducted studies and does not contain new data/results of human participants or animals performed by the author.

Literature Search Methods

In this narrative overview of article(s) the following selection criteria were used: Inclusion criteria included (a) clinical studies using pre-, peri-, or postmenopausal women, (b) literature reviews on the effects of bioactive compounds (phytoestrogens, etc.) on human skin and skin aging, and (c) in vitro or in vivo clinical studies that examined the effects of bioactive compounds/phytoestrogens and skin parameters. Exclusion criteria included (a) clinical studies with hormone and/or menopause replacement therapy, (b) case reports, (c) and in vitro or clinical studies using 17β-estradiol or any estrogen analogue(s) as the treatment, (d) animal studies, and (e) duplicate articles.

Skin Characteristics

Skin covers an area of approximately 2 m² (however, more recent estimates accounting for dermal pores suggest 25 m², which approximates the area of the gastrointestinal tract at 30 m²), and skin represents one-sixth of the total body weight for an adult [8]. General skin layers are displayed in Fig. 1 [4, 8, 9].

Fig. 1.

Human skin characteristics. The epidermis receives no blood supply, while the dermis and hypodermis have a rich blood supply. Thus, topical care from outside to inside the skin is traditional, whereas oral nutraceutical supplement care from the inside to outside is more limited but represents a novel innovation for improved dermal health. Adapted, modified, and expanded from Knaggs and Lephart [23], license under CC BY 4.0

There are three general dermal areas, (1) the epidermis, (2) the dermis, and (3) the hypodermis [8–10]. Each skin layer contributes differently to the maintenance of skin-tissue homeostasis [11–14].

The outermost layer, the epidermis, provides a physical barrier, consisting of densely packed keratinocytes devoid of a blood supply [4, 8–10]. The epidermis protects against foreign agents (pathogens), ultraviolet (UV) light, chemicals, as well as mechanical or other trauma. Plus, this outer skin layer is where vitamin D is produced [4, 8, 9, 11–14]. The epidermis also prevents transepidermal water loss (TEWL) that ranges from 120 to 240 g per square meter per day and maintains hydration and body temperature [9, 10].

The dermis is composed of a matrix of collagens and elastin fibers [4, 8, 9]. These fibers are surrounded by glycoproteins, proteoglycans, and glycosaminoglycans [4, 8, 9]. While the epidermis is devoid of a blood supply, the dermal region contains capillaries [4, 8, 9]. These fibers represent the skin’s mechanical properties of strength and elasticity that provide support and flexibility [4, 8, 9]. The major structural protein of the dermis is collagen type I, which accounts for up to 80–90% of the dermal matrix. The remainder of the dermis is mostly collagen type III [4, 8, 9]. The dermis also detects/fights infections and provides sensory information via the mechanoreceptors (touch, pressure, temperature, and pain-nociception) [4, 8, 9]. The hypodermis is composed of loose connective tissue, larger blood vessels, lymph vessels (for immune function), and nerve fibers (compared to the dermis) plus fat (or adipose tissue) that insulates the body, stores energy, and provides a cushion component associated with the skin [4, 8, 9, 12].

Skin biology represents challenges for both topical and oral supplement applications. For example, Woodby et al., in 2020 [12] in their journal report entitled “Skin health from the inside out,” stated: “unfortunately, dietary intervention alone [13] is inadequate to prevent/treat skin conditions, primarily due to skin biology…. The outermost layers of the epidermis are removed from the blood supply and ensuing nutrient delivery. Furthermore, the barrier function of the skin resides in the outer layers of the skin, which can prevent diffusion of molecules from the underlying dermis. Thus, it is likely that a two-pronged approach, utilizing both topical applications and dietary intervention, is needed for optimal nutrient delivery to the skin. For example, in clinical trials, combinatory oral and topical supplementation with lutein and zeaxanthin provided the highest degree of antioxidant protection.”

Skin Aging in Women

The signs of skin aging in women can vary with the passage of time, but in general, some aspects include distinct changes for each decade of life. For example, women in their twenties have skin tone and dermal texture that are healthy [4, 8, 9, 15, 16]. By age 30, women notice the appearance of wrinkles, changes in pigmentation, further skin tone alterations, and enlarged facial pores [9, 17–19]. This is due to the changes in hormone levels, which will be covered in the next section, but more importantly, apply for each subsequent decade of life. Women in their forties notice a declining appearance of their facial areas with drier skin and more pronounced wrinkles [4, 8, 9, 17]. But the greatest reduction in skin health is observed when women turn 50 and experience menopause, which has a dramatic negative impact on skin aging due to the loss of estrogen production from the ovary [4, 8, 9, 20]. Women in their sixties and beyond experience thinning of the skin (fragile, age spots and bruises become more noticeable) with delayed wound healing along with reduced ability to sense touch, pressure, temperature, etc. [4, 8, 17, 20–22].

Also, lifestyle factors can play an important role in skin aging and health in general. These include diet, lack of sleep, stress, genetics, and especially exposure to the damaging rays of sunlight that will be covered in more detail below [23]. In examining this aspect with reference to skin aging, Wong and Chew, in 2021, reported via a systematic review and meta-analysis that seven notable risk factors were identified, which are not ranked but included (1) age, (2) gender, (3) ethnicity, (4) air pollution, (5) nutrition, (6) smoking, and (7) sun exposure [24].

Chronological (Intrinsic) Skin Aging and Photoaging (Extrinsic) Skin Aging

Intrinsic or chronological aging is the natural process with the passage of time that causes inflammation with the production of reactive oxygen species (ROS) resulting in oxidative stress from oxidative cellular metabolism [4, 8, 9] and is influenced by genetics, metabolism, hormonal, immunological, cardiovascular, gastrointestinal, psychogenic (involving stress or affective disorders), degenerative, or neoplastic disease [23–25]. For example, Fig. 2 displays the split-face photograph of a Caucasian woman at age 23 (on the left) compared to the same woman at 61 years of age (on the right). The cascade of events of intrinsic aging plays a minor role with increased inflammation leading to oxidative stress via the formation of ROS, which in turn stimulates matrix metalloproteinases (MMPs) that are enzymes that break down collagen and elastin fibers in the skin and create increased wrinkles and poor skin health [4, 8, 9, 15, 17, 23].

Fig. 2.

Examples of chronological (intrinsic) aging and photoaging (extrinsic) aging are displayed in this split-face photograph of a 23-year-old Caucasian woman (left) compared to the same woman at 61 years of age (right). Photoaging is the most damaging to skin health [25]

Reproduced with permission from MedSkin (Nkengne and Bertin 2012) which is given in Lephart [25]

On the other hand, extrinsic or photoaging plays a major role in damaging the skin, which is due to the exposure to the UV rays of the sun that activate the same cascade of events (seen in chronological aging) but to a much greater extent because most dermatologists agree that 90% of skin aging is due to photoaging [4, 7–9]. As shown in Fig. 2, on the right, the split-face photograph, the same woman now at 61 years of age displays a sagging jawline, uneven skin tone and texture, solar elastosis, and wrinkles and decrease skin turgor [25]. Both chronological aging (or intrinsic aging) and photoaging (or extrinsic aging) have been reported in detail elsewhere [4, 8, 9, 15, 17, 24, 25].

Changes in Hormone Levels with Aging in Women and the Impact on Skin Health

The most dominant hormonal influence on skin aging is estrogen, more specifically 17β-estradiol, which is the most potent sex steroid hormone in humans [4, 8, 26]. It is the major estrogen produced by the ovaries during the reproductive years [4, 8, 26, 27]. The numerous physiological and cutaneous benefits of 17β-estradiol have been reported elsewhere [4, 8, 28–30].

The profile for 17β-estradiol displays maximal levels around the mid to late 20 s in women (Fig. 3) [4, 8, 27]. Around 30 years of age, estrogen levels begin to decline, and there are corresponding changes in the skin; wrinkles begin to appear because of the decline in collagen and elastin fibers in the dermal layer [4, 8, 9, 15, 17, 27]. 17β-Estradiol production from the ovarian follicles declines further after 35 years of age, and there is a progressive decline in estrogen levels at 40–45 years of age (Fig. 3) [4, 8, 20, 26]. Thereafter, there begins to be inconsistent oscillations in ovarian estrogen production as the follicles respond to gonadotrophins, especially waves of follicle stimulating hormone (FSH), until the follicles become exhausted and/or unresponsive with the onset of menopause (in the USA this milestone is around 51 ± 4 years of age) [4, 8, 20, 27]. After menopause, estrogen production occurs not in the ovaries but at peripheral adipose tissue sites [4, 8, 27]. While it is known that skin cells can produce estrogens locally, the amount or level of estrogen synthesized there is very low and the estrogen produced is estrone, which has 1/10 th of the biological activity of 17β-estradiol. Therefore, if one compares the production of estrogen in skin to that of ovarian follicular tissue in the premenopausal interval the biological activity of ovarian derived 17β-estradiol is approximately 30 times greater compared to estrone derived from dermal cells [4, 8, 26]. Although estrogens play a leading role in skin, other hormones also have a substantial influence on dermal health [20, 23].

Fig. 3.

Representative changes in hormone levels with age in women. Estrone (E1) is the primary estrogen after menopause that has approximately 1/10 th the biological activity of 17β-estradiol. The values of the hormones shown in this figure represent, in general, averages from various journal reports [4, 8, 27, 33–35]

The profile of progesterone (P4) levels (in nonpregnant women) is somewhat different compared to estrogens. Progesterone originates mainly from the ovaries with a small contribution from the adrenals, which decreases by about 50% by age 40 [27, 31] and then continues to decline to very low levels after menopause (Fig. 3) [27, 31]. While progesterone can have several positive benefits for skin aging including increasing skin elasticity and firmness, reducing inflammation, stimulating collagen and enhancing wound healing [32], the major hormonal factor involved in skin aging is the loss of estrogens [4, 8, 28–30].

Male steroid hormones, androstenedione (A) and the principal androgen, testosterone (T), originate from the ovaries and adrenals before menopause and then mainly from the adrenals and peripheral tissue sites after menopause (Fig. 3) [27]. Androstenedione levels are approximately four times that of testosterone before menopause, but both androgens are reduced by around 50% by age 50 at menopause and continue to decline thereafter [27, 33]. However, there is one report that showed testosterone levels in women after age 60 displayed a slight increase, suggesting that the loss of estrogens with menopause along with the negative impact of androgens contributes to advance skin aging [34]. This is particularly significant since the 5α-reductase enzyme in dermal fibroblasts can convert testosterone to 5α-dihydrotestosterone (5α-DHT), which is 2.5 to 5 times more potent than testosterone, to cause considerable negative impact on dermal health [35]. Finally, to illustrate the importance of estrogen as a hallmark of aging, Fig. 4 displays the pleiotropic impact estrogen deficiency has on 27 different dysfunctions in cellular, metabolic, physiological, and molecular mechanisms [4, 8, 36–38].

Fig. 4.

Estrogen deficiency is a pleiotropic factor in the hallmark of aging in women. This figure displays the multifactor influences of the lack of estrogen as women age, which have been adapted, modified, and expanded from that described by Kennedy et al. [36] and Schmauk-Median et al. [37], licensed under CC BY 3.0, and Zomer and Cook [38], licensed under CC BY 4.0

Characteristics of Bioactives with Estrogenic Properties (Phytoestrogens)

The National Cancer Institute (NCI) of the National Institutes of Health (NIH) in the USA defines bioactive compounds in the following manner: “A type of chemical found in small amounts in plants and certain foods (such as fruits, vegetables, nuts, oils, and whole grains). Bioactive compounds have actions in the body that may promote good health. They are being studied in the prevention of cancer, heart disease, and other diseases” [39].

Although many bioactive compounds may enhance skin attributes, the main element to consider is the estrogenic hormonal actions of such compounds. Polyphenols and phytoestrogens fit this characteristic due to their similar chemical structure to 17β-estradiol and ability to bind and/or active estrogen receptors in skin [7, 8]. These characteristics have been reviewed in detail elsewhere [7, 8, 40].

Notably, estrogen therapy, whether for men or women, can cause various side effects including mood changes, breast tenderness, nausea, and increased risk of blood clots or certain cancers. The specific effects and risks can vary depending on the individual and the type of therapy [41].

However, bioactives with estrogenic properties such as polyphenols and/or phtyoestrogens not only have been shown to have health benefits but in many cases they are also used with known anticancer agents like tamoxifen to treat certain cancers more efficaciously [42, 43].

The Most Common Phytoestrogens in Skin Treatments

There are four principal classes of phytoestrogens: (1) flavonoids, (2) phenolic acids, (3) lignans, and (4) stilbenes [7, 40]. However, the most common phytoestrogens in skin treatments include the isoflavonoids (daidzein, genistein, and equol) and the stilbean (resveratrol) according to the search criteria used for this narrative overview. Recall that plants do not make estrogens but contain compounds that are estrogen-like or estrogenic, and if the bioactive compounds have a higher affinity for ER subtypes (ERα or ERβ), then they are classified as SERMs [7, 40, 44]. Remarkably most isoflavonoids have a higher affinity for ERβ (versus ERα), whereas resveratrol is a mixed agonist for ERα and ERβ [7].

In Vitro Human Skin Cell Studies and the Cellular/Molecular Actions of Isoflavonoids and Resveratrol

Several studies have demonstrated the antioxidant and anti-inflammatory properties of isoflavonoids and resveratrol, but the common protective action for skin health is the reduction in oxidative stress, which plays a critical role in human skin aging and dermal tissue damage [4, 7, 40, 44–49]. A summary of the antiaging effects of the most common phytoestrogens (daidzein, genistein, equol, or resveratrol) in skin treatments are displayed in Table 1 [7, 40, 44–49]. For example, isoflavonoids and resveratrol are known to stimulate the expression of SIRT1, collagen, elastin, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), Nrf2, SOD, PCNA, VEGF, TGFβ, NGF, and CAT. Also, these phytoestrogen classes have been shown to inhibit inflammation, NFkappB to decrease ROS, matrix metalloproteinases (MMPs), and protein S100-A8 and S100-A9, while protecting DNA and enhancing tissue repair to ameliorate photoaging. Finally, only equol has been shown to inhibit the expression of the 5α-reductase enzyme in skin and bind selectively to free 5α-DHT [40, 44–49].

Table 1.

Cellular, biochemical, and molecular antiaging actions of common isoflavonoids and resveratrol in skin therapies/treatments

Actions	Isoflavonoids	Resveratrola	Reference(s)
Stimulates SIRT1	Equol	X	[7, 40, 45]
Stimulates collagen and elastin	Daidzein, equol, genistein	X	[7, 40, 44]
Stimulates TIMP-1	Daidzein, equol, genistein	X	[7, 40, 44]
Stimulates VEGF and TGFβ	Isoflavonoid mixture, genistein		[41, 47, 48]
Stimulates fibrillin-1	Daidzein		[44]
Stimulates Nrf2 (↑ antioxidants)	Equol	X	[7, 40]
Stimulates superoxide dismutase (SOD)	Equol	X	[7, 40]
Stimulates nerve growth factor (NGF)	Equol	X	[7, 40]
Stimulates catalase (CAT)	Equol	X	[7, 40]
Stimulates PCNA	Equol, genistein	X	[7, 40]
Inhibits S100-A8 and S100-A9 (aging factors)	Equol, genistein	X	[7, 40, 42]
Inhibits inflammation (interleukins-1, 6, and 8 and AP1)	Equol, genistein	X	[7, 40, 44, 45, 47]
Inhibits NFkappB (↓ ROS)	Equol, genistein	X	[7, 40, 44, 45, 47]
Inhibits MMPs (MMP1, 3, and 9 to protect collagen and elastin)	Equol, genistein	X	[7, 40, 44]
Inhibits 5α-reductase enzyme expression	Equol		[7, 40]
Inhibits cyclooxygenases (COX-1)	Equol, genistein	X	[7, 40, 44, 49]
Binds to free 5α-DHT	Equol		[7, 40]
Protects against photoaging	Daidzein, equol, genistein	X	[7, 40, 44, 45, 47, 49]
Protects DNA and enhances tissue repair	Daidzein, equol, genistein		[7, 40, 44, 45, 47, 49]
Delays skin aging	Daidzein, equol, genistein	X	[7, 40, 44, 45, 47, 49]

SIRT1 sirtuin 1 (antiaging factor); TIMP-1 tissue inhibitor of matrix metalloproteinase 1 (inhibits breakdown of collagen and elastin); VEGF vascular endothelial growth factor (enhances blood vessel density); TGFβ transforming growth factor-β (enhances collagen production); Nrf2 nuclear factor-erythroid 2-related factor 2 (master switch to turn on antioxidant production); PCNA proliferating cell nuclear antigen (antiaging factor, reduces wrinkles); NFkappB nuclear factor kappa-light-chain enhancer of activated B cells (inflammatory signal); MMPs matrix metalloproteinases (enzymes that breakdown collagen and elastin fibers); 5α-DHT 5α-dihydrotestosterone (the most potent androgen, male hormone that has negative effects on skin)

^aX under the resveratrol column indicates that resveratrol has the action listed in that row

Topical Clinical Studies of Phytoestrogens for Improved Dermal Health in Estrogen-Deficient Skin

Percutaneous Absorption of Phytoestrogens in Human Skin

Several studies have examined the percutaneous absorption of isoflavonoids and resveratrol [50–52]. These studies demonstrated that these polyphenolic compounds penetrate human skin and/or can be enhanced by dermal-penetrating agents or microencapsulation [50–52]. However, only equol has been shown to have unique delivery properties into human skin, where it forms a reservoir in the epidermis and then is slowly released into the dermis over a 28-h interval with a single topical dose [50]. This slow dermal release mechanism of equol is due to binding the predominate ERβ in the epidermis that builds up and then is slowly released into the dermis, which is based upon percutaneous investigations using [³H]-equol as the tracer in Franz cell testing protocols [50].

Topical Clinical Studies

The literature search revealed 12 clinical studies examining topical phytoestrogen treatment(s) in women (Table 2). While the clinical investigations varied in several ways, it should be noted that most of the studies were clinical observations where there were no adverse events reported, and all the treatments were well tolerated. In a few clinical studies skin samples were processed for histological analysis and dermal protein characteristics were quantified, which are noted below.

Table 2.

Clinical studies: topical phytoestrogen treatment(s) in women

Authors	Treatment(s)	N	Age (years)	Time (weeks)	Area	Outcomes
Bayerl and Keil [53]	Cream phytoestrogens*	234	53–65	12	Face	Improved skin dryness, roughness, skin turgor/texture, and decreased wrinkles
Moraes et al. [55]	Gel (isoflavones—4% genistein)	18	PMW	24	Face	Increased epidermal thickness, fibroblasts, and dermal papillae
Patriarca et al. [56]	Gel 4% genistein	15	PMW	24	Face	Increase in hyaluronic acid and fibroblast levels
Farris et al. [62]	Cream 1% resveratrol, 0.5% baicalin, and 1.0% vitamin E	55	40–60	15	Face	Improvement in wrinkles, firmness, elasticity, pigmentation, radiance, and smoothness
Silva et al. [57]	Gel 4% genistein	15	45–55	24	Face	Increase in collagen type I and III production
Magnet et al. [58]	Cream equol (unknown)	64	40–60	8	Face	Improvement texture, elasticity, firmness, increased telomere length and decreased methylation
Brinke et al. [59]	Emulsion 2% resveratrol	20	30–35	8	Face	Improvement elasticity, smoothness, thickness, skin density, and barrier function
Lephart and Naftolin [4]	Cream 1% 4′-acetoxy-resveratrol	36	34–60	12	Face	Improvement in eight skin parameters from skin firmness, tone, wrinkles, and hydration
Lephart and Naftolin [4]	Cream 0.3% equol	59	40–70	12	Face	Improvement in eight skin parameters from skin smoothness, tone, wrinkles, and hydration
Lephart [7, 60]	Cream 0.15% equol (only)	49	40–70	12	Face	Improvement in eight skin parameters—as above
Lephart [7, 60]	Cream 0.15% equol plus other natural ingredients	42	40–70	12	Face	40% Improvement over the eight skin parameters (equol plus vitamin C, grape seed and hyaluronic acid) compared to equol treatment alone, 78% Women were postmenopausal
Takuathung et al. [61]	Cream 4% genistein, 1% vitamin E and B3, 0.2% ceramide	50	48–65	6	Face	Some skin redness in the genistein group compared to placebo controls. However, hydration and wrinkles improved with a decrease in skin pores

In a few studies, estradiol (0.01%) was used as a topical treatment but not noted in this table (see text Moraes 2009 [55], Patriaca 2013 [56], and Silva 2017 [57], for specific details)

PMW postmenopausal women

*Cream phytoestrogen levels are unknown, based upon the English translation of this German dermatology report

For example, the first study by Bayerl and Keil, in 2002, was part of a controlled, open multicenter study in eight different European clinics in Germany, France, Italy, Switzerland, and Spain that examined a personal care product containing isoflavones [50]. This study, reported in a German scientific journal, examined 234 women, who had been through menopause for at least 3 years and were up to 65 years of age. After 12 weeks of the topical phytoestrogen–isoflavone application, the positive outcomes included improved skin dryness and roughness along with a reduction in facial wrinkles and an increased skin turgor and texture [53]. However, the concentration(s) of phytoestrogens (isoflavones) used in this study were not reported. Unfortunately, in a subsequent review by Rzepecki et al. in 2019 [54], they erroneously reported the concentration(s) of isoflavones used in the Bayerl and Keil study as 0.0075% or 0.015%. Upon examining the English translation of this German scientific publication, the percutaneous absorptions rates were reported, but the topical phytoestrogen (isoflavone) cream concentrations used were not provided [50]. Rzepecki et al. [54] apparently used the absorption rates from the Bayerl and Keil study as the concentrations of phytoestrogens in the topical cream applications [53]. Therefore, the Rzepecki et al. 2019, review [54] of the Bayerl and Keil study is apparently in doubt pertaining to what levels of active ingredients (isoflavones) were in the cream applications in this German study [53], and the true significance of this clinical skin study remains unknown (see Table 2).

In a double-blind, randomized clinical investigation by Moraes et al., in 2009 [55], the study was designed to analyze the effects of topical administration of estradiol gel (0.01%) versus a (4%) genistein gel that was applied topically to the facial area of 18 postmenopausal women (PMW) per treatment group for 24 weeks [55]. Skin biopsies were performed on each subject before and after the treatments. The skin samples were processed for histological analysis and examined using light microscopy. The estradiol group displayed a 75% increase in epidermal thickness compared to a 20% increase in the genistein group, and similar data were observed for the number of dermal papillae, fibroblast gain, and improvement in dermal vascularization between the treatment groups [55] (Table 2). The conclusion of this study was that estrogen had a stronger effect on the histomorphometic parameters compared to isoflavones.

Patriarca et al., in 2013, reported a prospective, randomized, double-blind study of 15 postmenopausal women, where the aim of this work was to compare the effects of estradiol (0.01%) and genistein (4%) treatments on skin hyaluronic acid concentrations [56]. After 24 weeks of treatment, hyaluronic acid concentrations increased in both treatment groups, but the effect was greater in the estradiol (0.01%) treatment than for the (4%) genistein group. Thus, this study reported increased hyaluronic acid and enhanced fibroblasts function in the dermal region in both treatment groups [56].

In a randomized, double-blind clinical study of 30 patients between the ages of 45 and 55 years old, Silva et al., in 2017, compared the effects of topical estradiol (0.01%) vs. topical genistein (4%) for 24 weeks on skin collagen (type I and type III) in postmenopausal women [57]. The topical estradiol (n = 15) and topical genistein (n = 15) treatments both significantly increase collagen levels in facial skin. Notably, serum estradiol levels were quantified before and after the 24-week treatment interval and stayed below 20 pg/ml, and there were no changes in endometrium thickness that inferred the topical estrogen or genistein produced no significant systemic side effects [57] (Table 2).

The first study to publish promising results of topical equol administration was reported by Magnet et al., in 2017 [58]. They showed topical equol administration (applied twice per day) for 8 weeks in 64 women (40–60 years of age) improved the structural and molecular skin parameters (roughness, texture, smoothness, firmness, elasticity) and decreased methylation and significantly increased telomere length in skin cells [58]. Additionally, the women did not show a significant difference in topically applied equol versus microencapsulated equol. This suggested that the delivery of equol was not enhanced by microencapsulation [58], which may relate to its unique dermal delivery mechanism over time where it accumulates in the epidermal layers and then is slowly released into the dermis [50] (see Sect. “Percutaneous Absorption of Phytoestrogens in Human Skin”).

In another topical study that specifically examined a 2% emulsion of trans-resveratrol, Brinke et al., in 2021, reported that applying the treatment twice daily for 8 weeks in 20 women (30–35 years of age) resulted in significant improvements in the quantified parameters of skin elasticity, barrier function, smoothness, thickness, and density without adverse events [59]. From this study, the skin improvements can be directly related to the resveratrol treatment, since both expert and participant evaluations showed similar data outcomes.

A topically applied resveratrol treatment involved evaluating an analogue of resveratrol, 4′-acetoxy-resveratrol (4 AR), in a randomized, single-center, 12-week study of 36 women (ages 34–64 years old, where 56% of the women were postmenopausal for at least 2 years) with mild to moderate skin aging [4]. A 1% 4 AR cream applied to the face/neck region twice per day for 12 weeks significantly enhanced skin parameters including skin firmness, smoothness, even tone, wrinkles, radiance, pore size, spots/discoloration, and hydration that ranged from 63% to 83% improvement over baseline [4], suggesting this resveratrol analogue may be beneficial in estrogen-deficient skin (Table 2).

In a second study examining equol, Lephart and Naftolin, in 2021, reported on a randomized, 12-week, single-center study of 59 women (ages 40–70 years old, where 76% of the women were postmenopausal for at least 3 years) with mild to moderate skin photoaging [4]. This represented 45 women that were postmenopausal, and 14 women classified as perimenopausal. The aim of this study was to determine the effectiveness of a 0.3% equol lotion applied to the face/neck twice daily after 12 weeks. The results showed significant improvement in the skin parameters firmness, smoothness, even skin tone/discoloration, lines/wrinkles, radiance, pore size, and hydration that ranged from 51% to 78% over baseline values [4]. The conclusion of this clinical investigation suggested a low dose of topical equol may benefit skin health in estrogen-deficient skin.

In 2021, Lephart reported a 12-week, single-center study of 42 women (40–70 years of age, 33 of whom were postmenopausal and 9 women were perimenopausal) [7]. The purpose of this study was to determine the effectiveness of a topical nutricosmeceutical containing equol (at 0.15%) plus other natural active ingredients (e.g., grape seed extract, vitamin C, hyaluronic acid). These study results were compared to a previous study that only used an equol treatment alone. The results of the topical nutricosmeceutical containing equol and other active ingredients showed remarkable improvement over topical equol treatment alone (where 49 women, 40–70 years of age were tested) [7]. When the comparison of the two studies was made, the nutricosmeceutical equol plus other natural ingredients showed superior results over the equol treatment only group for skin firmness, smoothness, tone/discoloration, wrinkles, radiance, pore size, and hydration [7]. Undoubtably, this represents a synergistic mechanism by which nutricosmeceutical formulations can yield significantly greater improvement in skin health parameters compared to single active ingredient formulations. Specifically, this study comparison represents an almost 40% average increase among the eight skin parameters for overall improvement. In the study that examined the equol plus the natural ingredient topical application, the data was not analyzed in comparing the postmenopausal (n = 33) results to perimenopausal values (n = 9) for the quantified parameters. Notably, this last clinical data set was originally reported in 2021 by Lephart [60].

Finally, in 2023, Takuathung reported the efficacy and safety of a topical genistein treatment (for 6 weeks) containing vitamin E, B₃, and ceramide on skin health in postmenopausal women (48–65 years of age) in a randomized, double-blind, placebo-controlled clinical trial [61]. There were 25 participants in each of the treatment groups (control vs. genistein) with a mean age of 55.8 ± 3.4 years of age and the topical treatment was applied twice daily. The skin parameters were quantified at baseline, and then at 6 weeks, where skin redness was significantly higher in the genistein group compared to the placebo controls. However, hydration, fine pores, and wrinkles were improved with the genistein treatment, suggesting potential positive benefits for facial skin of postmenopausal women [61] (Table 2).

Oral Clinical Studies of Phytoestrogens for Improved Dermal Health for Estrogen-Deficient Skin

Pharmacokinetics and Bioavailability of Phytoestrogens via Oral Administration

Resveratrol is the most well-known phytoestrogen with significant biological and pharmacological properties [62–64]. However, while resveratrol has high oral absorption at approximately 70–75% in humans [65], it has very low bioavailability due to extremely rapid sulfate conjugation by the intestine/liver, which appears to be the rate-limiting step in resveratrol’s bioavailability (at approximately 1%) [66]. For example, an oral dose of 1000 mg yields a plasma resveratrol level of approximately 100 ng/ml or 23 nM [66].

Additionally, other factors that influence the efficacy of phytoestrogens include their binding to sex-hormone-binding globulin (SHBG). For example, SHBG binds sex steroids and phytoestrogens in blood, thereby regulating their bioavailability, because when bound they are biologically inactive. However, resveratrol is not bound by SHBG [67], while equol is bound at approximately 50% [67, 68]. Resveratrol is known to increase hepatic SHBG expression and may have health benefits, which might explain the positive effects of consuming red wine [67]. Conversely, low SHBG levels are associated with metabolic syndromes and other comorbidities particularly cardiovascular disease and type II diabetes [67].

Conversely, equol has a relatively high bioavailability compared to other soy isoflavones (like daidzein or genistein), meaning a significant portion of ingested equol is absorbed into the bloodstream largely owing to its unique structure that allows for efficient absorption (at around 80%) with minimal further metabolism once consumed [68–71]. Furthermore, almost 50% of equol circulates free (unbound to SHBG) compared to daidzein and genistein, which have higher portions bound to SHBG [68–70].

For example, the pharmacokinetics of free phytoestrogens are shown in Table 3, which are derived from various journal reports [67, 72, 73]. Notably, a 100-mg dose of equol yielded a mean peak plasma level of 986 nM compared to a similar dose of resveratrol that was 29 times lower at 34 nM. Also, at similar dosing, mean peak plasma equol levels were approximately 50% higher compared to daidzein or genistein values.

Table 3.

Mean pharmacokinetic characteristics of free phytoestrogen (resveratrol, daidzein, equol, and genistein)

	N	Mean plasma (nM)	Cmax (nM)	Tmax (h)	AUC (nM × h)	T1/2 (h)
Resveratrol 100 mg	15	34	3	1.6	8	6.4
Resveratrol 500 mg	15	171	16	1.4	41	5.1
Daidzein 50 mg	6	312	623	6.0	6629	8.1
Daidzein 100 mg	6	612	1146	6.3	14,683	13.1
Equol 50 mg	6	396	781	4.3	6510	8.8
Equol 100 mg	6	986	1928	4.7	17,567	7.1
Genistein 50 mg	6	282	570	9.0	5248	7.5
Genistein 100 mg	6	673	1147	6.0	16,747	14.5

The adult resveratrol data were collected from healthy male and female subjects and the 100-mg dose was calculated from Sergides et al. [72] using known pharmacokinetic profiles; the isoflavonoid data were obtained from peri- and postmenopausal women from Hernandez et al. [73] with permission, license ID 1563827-1

N  number of subjects; nM nmol/l; C_max maximum plasma concentration; T_max time to reach the C_max; AUC (nM × h) total area the plasma concentration–time curve; T_1/2 plasma half-life

Oral Clinical Studies

The literature search revealed nine clinical studies examining oral phytoestrogen treatment(s) in women (Table 4). The first clinical study (single center, double-blind, placebo-controlled) that examined the effect of a novel dietary supplement on skin aging in postmenopausal women was by Skovgaard et al., in 2006 [74]. There were 38 women in the treatment group and 42 women in the placebo control group with a mean age of 56 years old. The aim of this study was to quantify skin parameters (wrinkles, pigmentation, laxity, sagging, eye/facial tone, and overall appearance) as influenced by taking a dietary supplement (1200 mg) twice daily for 6 months containing soy extract, fish protein polysaccharides, extracts from white tea, grape seed and tomato, vitamins C and E as well as zinc and chamomile extract [74]. The results in the dietary supplement group displayed significantly greater improvement in the skin parameters versus placebo-controls, especially for decreasing wrinkles, pigmentation, turgor/sagging, under the eye dark circles, and significantly increased dermal density [74]. However, since a mixture of bioactives was used one cannot infer that the obtained results were due to phytoestrogens.

Table 4.

Clinical studies: oral phytoestrogen treatment(s) in women (and men)

Authors	Treatment(s)	N	Age (years)	Time	Area	Outcomes
Skovgaard et al. [74]	1200 mg soy isoflavone plus, other ingredients/day	42	40–65	6 months	Face	Improved wrinkles, pigmentation, turgor/sagging, under eye dark circles, and ↑ dermal density
Izumi et al. [75]	40 mg soy isoflavones/day	26	30–40	12 weeks	Face	Improved in skin turgor
Accorsi-Neto et al. [76]	Isoflavone supplement 100 mg/day	30	40–60	6 months	Face	Increase epidermal thickness, collagen and elastin deposition, dermal blood vessel density, ↓ wrinkles
Oyama et al. [77]	10 mg S-equol/day or 30 mg S-equol/day	101	45–60	12 weeks	Face	Improvement wrinkles, skin tone, hydration, elasticity, transepidermal water loss at both doses
Hausenblas et al. [78]	100 mg resveratrol and 1000 mg collagen/twice daily	29	36–76	6 months	Face	Improvement wrinkles, pores, and skin tone
Jenkins et al. [79]	Soy isoflavone supplements and nutraceutical drink, 2 capsules/day and 100 ml/day	159	45–71	14 weeks	Face	Improvement wrinkles and deposition of new dermal collagen
Davinelli et al. [80]	10 mg equol and 25 mg resveratrol/day	60	50–55	12 weeks	Face	Improvement in menopausal-related parameters (hot flashes, anxiety, depression, and skin health)
Lephart [81]	3 mg racemic equol/twice daily	22	37–54	12 weeks	Face	In men: Improvement in hydration, skin smoothness, tone, wrinkles, skin spots (discoloration)
Rizzo et al. [82]	Complex soy supplement with large number of active ingredients	44	50–70	6 months	Face	Improvement in wrinkles, pigmentation and hydration

Another clinical double-blind, placebo-controlled trial by Izumi et al., in 2007, investigated the effect of soy isoflavones on skin parameters in 26 middle-aged women (30–40 years old) that consumed a test nutrient (40 mg of soy isoflavones per day) for 12 weeks [75]. Skin parameters were assessed at 4, 8, and 12 weeks for linear and fine facial wrinkles and elasticity by standard methodology via photo analysis. There were significant differences between the test food group (n = 13) compared to the control group (n = 13) where fine wrinkles and skin elasticity were improved along with enhancement of skin turgor in the test food group [75].

Accorsi-Neto et al. published the next clinical study, in 2009, that evaluated the effects of dietary isoflavone supplement (100 mg/day) for 6 months in 30 postmenopausal women (40–60 years of age) [76]. Morphometric determination via skin punch samples showed that the isoflavone supplement significantly increased epidermal thickness, collagen and elastin deposition, dermal blood vessel density, and significantly decrease skin wrinkling in most of the treated women (86%) [76].

In 2012, Oyama et al. examined postmenopausal women, in a pilot randomized placebo-controlled trial for 12 weeks in 101 Japanese women who were equol non-producers [77]; 34 subjects in the placebo group, 34 subjects receiving the 10-mg dose of S-equol, and 33 subjects receiving the 30-mg dose of S-equol per day [77]. (See reference [70] for the definition of “non-equol producers.”) However, in brief, approximately 20–50% of humans after consuming soy or other plant food products containing phytochemicals are equol producers [70]. Equol, produced from daidzein, in an isoflavonoid metabolite and equol producers that can maintain equol levels around or above 10 to 20 ng/ml in serum have protective health benefits [70]. Non-equol producers cannot metabolize daidzein in this manner. In the Oyama study, the skin parameters measured included crow’s feet wrinkles around the eyes (using silicon skin replicates), hydration, transepidermal water loss and elasticity, which significantly improved in both equol dosing treatments (i.e., 10 and 30 mg per day) compared to the placebo-control group values with no adverse events reported [77]. These data suggest that S-equol oral supplementation may have beneficial effects on skin health in postmenopausal women with estrogen-deficient skin [77].

Hausenblas et al., in 2013, reported in a prospective study that examined 29 women with visible signs of facial skin aging (36–76 years of age) that took two oral supplements daily for a total dose of 100 mg resveratrol plus 1000 mg of collagen [78]. After 6 months, the subjects had significant improvements in facial pores, ultraviolet spots, wrinkles, and skin tone with no adverse events reported [78]. In this report the authors made the admission that they did not know which active ingredient (collagen, resveratrol, or both) resulted in the positive improvements of the skin parameters. Thus, it is difficult to evaluate the true significance of this study based upon the multiple active ingredients tested in this investigation.

In 2014, Jenkins et al., reported a 14-week, double-blind, placebo-controlled study, which tested the effects of a combination supplement drink/capsules (composed of soy isoflavones, lycopene, vitamin C and E, and fish oil at 100 ml volume) at two different levels of the active ingredients [79] on skin parameters, see Table 5. There was a total of 159 postmenopausal women (ages ranged from 45 to 71 years of age) tested in this study; the treatment groups comprised 51 in supplement group 1 and 53 in supplement group 2 with 55 in the placebo-control group. Punch biopsies along with silicon skin replicates, at baseline and following 14 weeks of treatment, were obtained for skin parameter analysis. The dermal attributes quantified included wrinkle depth and the change in dermal collagen content. Plus, urinary daidzein and genistein levels were quantified by gas chromatography to determine the changes in the isoflavone levels by treatments compared to control values [79].

Table 5.

Study treatments and active ingredient dosing

Active ingredients (mg)	Placebo group	Supplement 1	Supplement 2
Total isoflavones (expressed as aglycone)	0	70 (43)	40 (25)
Lycopene	0	8	3
Vitamin C	0	250	140
Vitamin E	0	250	30
Omega-3 EFAs	0	660	660
Dose (quantity per day 100 ml drink)	1	1	1
Soft gel capsules	2	2	2

Omega-3 EFA (is alpha-linolenic acid or ALA). Adapted from Jenkins et al. [79] with permission license ID 1563856-1

The results showed a significant reduction in the depth of facial wrinkles, and this improvement was associated with increased deposition of new collagen fibers in the dermis of the supplement groups compared to the control values. The unique supplement drink/gel capsule treatments were validated by increased urinary daidzein and genistein levels with treatment groups [79], suggesting that consuming this novel oral supplement improves skin health parameters in postmenopausal women.

In connection with oral dosing of resveratrol and equol a report (in 2017) by Davinelli et al. studied 60 menopausal women (50–55 years of age) in a randomized, placebo-controlled investigation on the influence of supplementation with equol (10 mg) and resveratrol (25 mg) per day for 12 weeks on hot flashes, anxiety, depression symptoms, and skin benefits [80]. The authors concluded the 12-week dietary supplementation with a combination of equol and resveratrol significantly improved the menopause-related quality of life parameters in healthy postmenopausal women, suggesting the combination treatment was effective, but could not elucidate the mechanism(s) of action other than the known benefits of the phytoestrogens [80].

Lephart, in 2021, published the only placebo-controlled pilot study in men of the effects of an oral equol nutraceutical supplement (3 mg) taken twice per day (at breakfast and dinner) for 12 weeks on skin parameters [81]. The study included 11 placebo controls and 11 nutraceutical supplement participants (age ranging from 37 to 54 years). After 3 weeks and every 3 weeks thereafter up to 12 weeks, skin parameters were quantified by perceived improvement questionnaires over baseline. By 3 weeks, skin smoothness, frown lines/wrinkles, skin tone, discoloration, and hydration significantly improved over baseline values. By 12 weeks, all five skin parameters were significantly improved over baseline and placebo-control values [81]. This is the first study to demonstrate that short-term equol oral supplementation may improve skin health in men.

In a 6-month, randomized, double-blind, controlled study of 44 postmenopausal women (50–70 years old), Rizzo et al., in 2023, investigated the effects of a complex oral soy supplement (with a large number of active ingredients) on skin photoaging such as facial wrinkles, dyspigmentation, and other dermal parameters using facial modeling/analysis obtained from high resolution facial photography [82]. In the treatment group 17 subjects and in the placebo control group 14 participants completed the study. By 16 weeks and at 24 weeks several facial skin parameters significantly improved (in wrinkle severity, pigmentation, and hydration) in the oral supplement group over baseline and compared to the placebo-control values, while there were no significant differences in sebum production [82]. The authors concluded that oral soy supplementation with isoflavones may improve skin photoaging along with several dermal health biomarkers.

Study Strengths and Limitations

This narrative review updates the role of bioactives as antiaging dermal therapies for estrogen-deficient skin by reviewing topical and oral clinical studies. In many cases the women in the clinical studies were menopausal, which supports the present findings that bioactives with estrogenic characteristics improved skin appearance and dermal attributes in postmenopausal women. Moreover, one study reported clear benefits in middle-aged men.

However, in several clinical studies the number of test subjects was small, and the methodology/evaluation varied from study to study. For example, some included both instrumentation and subjective assessments of skin features, but in a few investigations the gold standard of skin punch sample analysis along with expert clinical graders or skin silicone casts were employed that supported the antiaging benefits of bioactives in women with estrogen-deficient skin.

Conclusions

Typically, estrogen-deficient skin in women is associated with peri- or postmenopausal intervals; however, estrogen levels begin to decline around 30 years of age, which defines a lack of estrogenic hormone action that has a significant impact on skin health [4, 8]. Therefore, several strategies to improve skin attributes have evolved with bioactives such as phytoestrogens that function as SERMs that bind specifically ERβ that are abundant in dermal layers [3, 6, 7] (Fig. 5). Since the epidermis is not exposed to a blood supply, topical applications to treat the skin from the outside to the inside have traditionally been used for millennia, while treating the skin from the inside to the outside via nutraceutical supplementation is a relatively new innovation. Treating the dermal layers from both sides is the best approach, and topical and oral (nutraceutical supplementation) therapies presented in this review focused on phytoestrogens for estrogen-deficient skin. While this is a growing area of research with promising results, more investigations are needed to understand the mechanism(s) of especially how combination active ingredient formulations work to improve skin health.

Fig. 5.

Summary of bioactives for estrogen-deficient skin

Author Contributions

Edwin Lephart planned, designed, performed searches, generated graphics, and wrote the manuscript (plus revisions) and provided permission/approval for this version of the review to be published.

Funding

This study was funded, in part, by the Life Sciences College, grant # 19-2215 at Brigham Young University. The publication fee was waived.

Data Availability

The data cited in this review are contained within the publications referenced.

Declarations

Conflict of Interest

The author declares no conflict of interest. Edwin D. Lephart is an Editorial Board member of Dermatology and Therapy. Edwin Lephart was not involved in the selection of peer reviewers for this manuscript nor any of the subsequent editorial decisions.

Ethical Approval

Not applicable. This review is based on previously conducted studies and does not contain new data/results of human participants or animals performed by the author.