The Therapeutic Role of Genistein in Perimenopausal and Postmenopausal Women

Abstract

Objective

We sought to review the biology and clinical benefits of genistein, a plant-derived isoflavone with emphasis on perimenopausal and postmenopausal women. The focus is on assessing its impact on skin health and aesthetics as well as bone density and cardiovascular and metabolic functions.

Methods

This narrative review used PubMed to collect studies relating to the biology and clinical effects of genistein on postmenopausal signs and symptoms, including bone density loss, metabolic issues and symptoms, and skin aging. Articles were selected based on relevance to the scope of genistein's influence on estrogen receptors and their downstream effects. This review included in vitro, in vivo, animal, and human studies.

Results

According to the current literature, genistein demonstrates efficacy in mitigating menopausal signs and symptoms such as hot flashes, bone density loss and rate of osteoporosis, and skin aging. It shows a protective effect against cardiovascular diseases by improving lipid profiles, weight changes, and reducing low-density lipoprotein cholesterol. It also displays benefits in increasing bone mineral density but has not displayed the side effects commonly associated with estrogen replacement. Regarding skin health, genistein appears to enhance photoprotection, wound healing, elasticity, and hydration, inhibits skin cancer, and reduces wrinkles.

Conclusion

Genistein acts as a selective estrogen receptor modulator (SERM) with benefits across a spectrum of menopausal signs and symptoms, presenting a viable alternative to estrogen replacement in perimenopausal and postmenopausal women. Its utility extends to improving cardiovascular health, bone density, and skin quality, making it a comprehensive treatment option for peri and postmenopausal women.

As humans age, virtually all organ systems lose their full functional ability. Bone loss and cardiovascular compromise are common; and skin becomes thinner, drier, and less elastic. This decline in structure and function is tied to the cumulative effects of factors like time, photoaging, hormonal imbalances, environmental stressors, and metabolic slowing.^1,2 In women, many deleterious organ system changes are emphasized during and after menopause, the natural end of menstruation due to ovarian failure, which occurs at a mean of 51.5 years of age in Western societies.³ The process of menopause causes significant fluctuations followed by sustained declines in ovarian hormones. Decreases in the sex hormone estrogen have been linked to numerous physiologic effects, including vasomotor symptoms (VMS), an increased risk of cardiovascular disease, bone loss and increased risk of significant osteoporosis, and changes to the skin.⁴ Management of declining estrogen levels through exogenous hormone supplementation has been shown to mitigate some of the effects of menopause; however, estrogen supplementation is associated with an increased risk for blood clots (including heart attacks and strokes), weight gain, and breast and endometrial cancers, and some women elect not to treat their menopause symptoms because of these associated risks. Therapeutic alternatives to estrogen supplementation with better risk profiles may make clinical improvements and symptomatic relief more accessible for women in menopause or the post-menopausal period.⁵

Flavonoids stand out as a potential alternative to exogenous estrogen supplements. Certain flavonoids are considered to be phytoestrogens, plant-produced compounds whose structural characteristics enable them to mimic the hormonal functions of endogenous estrogens. Derived from a wide range of plants, flavonoids are abundant polyphenolic compounds commonly associated with various health-promoting effects, including anti-inflammatory, anti-cancer, and antioxidant activities. Isoflavones, which are a structural subgroup of flavonoids, are among the more biologically active phytoestrogens and exhibit selectivity to which estrogen receptors they bind, with a preference for estrogen receptor (ER) beta (ERβ) over ER alpha (ERα). Evidence suggests that the selective estrogenic activity of isoflavones may provide clinical improvements and symptomatic relief for patients with an estrogen deficit, without the risk associated with typical estrogen supplementation.⁶

Genistein (5,7,4'-trihydroxyisoflavone), found in soybeans and other legumes, is an isoflavone that functions as a selective estrogen receptor modulator (SERM) with a preference for ERβ.⁶ By activating ERβ, genistein triggers several pathways that mitigate the effects of unopposed estrogen, such as by modulation of cell proliferation and apoptosis, which are critical factors in estrogen-associated cancer development and progression.^7,8 Currently, genistein is used clinically as the main ingredient of two medical foods indicated for osteoporosis.⁹ Genistein aglycone is available as prescription medical food in combination with vitamin D3 and zinc (Fosteum; Primus Pharmaceuticals) or in combination with phosphate, zinc, calcium, vitamins D3 and K2 (Fosteum Plus; Primus Pharmaceuticals). Medical foods are intended to provide a targeted nutrient-oriented therapeutic approach, must be administered under a physician’s supervision, and are available by prescription only for specific disease states.^10,11 Evidence indicates that the effects of genistein-based medical foods are pleiotropic, and they may include protective health benefits in osteoporosis, obesity, diabetes mellitus, hyperlipidemia, and cardiovascular disease.¹² Furthermore, as an antioxidant, genistein may protect against ultraviolet (UV)-induced skin damage, and it could also reduce the risk of diseases associated with oxidative stress, such as heart disease and cancer.⁷ Genistein also appears to improve skin elasticity and enhance collagen synthesis, showcasing its utility in mitigating the effects of skin aging.³ This review will focus on the therapeutic role of genistein in perimenopausal and postmenopausal women as an anti-aging and regenerative treatment through exploration of its potential applications, analysis of its proposed mechanisms of action, and narrative review of existing evidence on its clinical efficacy.

METHODS

A narrative literature review was conducted on PubMed to examine the effects of genistein on multiple organ systems, including the skin. This review was based on articles sourced through targeted searches using terms like "Genistein AND skin," "Genistein AND osteoporosis," "Genistein AND vasomotor symptoms," "Genistein AND metabolic issues," "Genistein AND prostate cancer," and "Genistein AND fertility." The search included articles pertaining to in vitro, in vivo, animal, and human studies. The review specifically excluded non-English articles and studies involving mixed isoflavones, focusing solely on studies discussing pure genistein. Further investigation into genistein's effects on the various organ systems was enhanced through citation tracking, additional PubMed searches, and consultations with experts.

Biochemistry of estrogen and genistein. Estrogen plays a complex role in regulating multiple organ systems such as the skeletal, cardiovascular, central nervous, and integumentary systems. Therefore, estrogen deficiency secondary to menopause can have several negative consequences. Effects across these organ systems can differ, through estrogen’s various interactions with its receptors.¹³ Estrogen's effects are mediated through two receptors: ERα and ERβ.¹⁴ These receptors act as transcription factors when bound to estrogen, regulating targeted genes. ERβ, prevalent in adult human bone, skin, and in cells like the outer root sheath and epithelial matrix, contrasts with ERα, which is mainly found in the dermal papilla cells of hair follicles.^14–17 The widespread distribution of estrogen receptors in the skin could benefit greatly from estrogen replacement, if not for the significant potential adverse effects associated with this treatment option, such as weight gain, breast cancer, endometrial cancer, and cardiovascular disease (Table 1).^5,18–21

TABLE 1.

Effects of estrogen replacement therapy versus genistein

EFFECTS	ESTROGEN	GENISTEIN
Body Mass Index	-/↑	↓
Bone loss	↓	↓↓
Breast cancer	-/↑	↓
Endometrial cancer	-/↑	↓
Heart disease	-/↑	↓
Hot flashes	↓	↓

Genistein's molecular structure allows it to mimic estrogen, engaging estrogen receptors with significant biological effects. It shows a strong preference for ERβ over ERα, with about 30 times greater affinity. When bound to ERβ, genistein alters the conformation of helix 12 in the receptor's active site to resemble an antagonist, despite its structural similarities to estradiol, the primary human estrogen. Functioning as a partial agonist for ERβ, genistein achieves 60 to 70 percent of estradiol's efficacy. This unique interaction with helix 12 highlights genistein’s distinct influence on estrogenic activities, emphasizing its nuanced role (Table 2).³

TABLE 2.

Relative binding affinity of genistein

COMPOUND	ERα	ERβ
17β-Estradiol	100	100
Raloxifene	69	16
Genistein	4	87

Genistein exists primarily in two forms: glycosylated genistein and aglycone genistein, with the latter being crucial for biological studies due to its higher bioavailability. Once ingested, aglycone genistein is absorbed in the intestines, conjugates with glucuronic acid, and may be transported to the liver and secreted into the bile for further intestinal metabolism and reabsorption.²² Comparative studies show that aglycone genistein is absorbed more effectively than glycosylated genistein due to its lower molecular weight and less hydrophilic nature, making it a focal point for extensive research in both preclinical and clinical settings.²³

Genistein for osteoporosis. Osteoporosis poses a significant health issue for the aging population globally, especially postmenopausal women.²⁴ Treatments such as hormone replacement therapy (HRT), bisphosphonates, calcitonin, and SERMs necessitate prolonged dosing schedules, provide limited symptom relief, and may have associated side effects.²⁵ Soy protein consumption in postmenopausal women correlates with increased bone mineral density (BMD), and isoflavones such as genistein have promising effects in treating postmenopausal osteoporosis.^26–28 Bone primarily contains ER-β receptors, which genistein binds to more effectively, potentially acting as an agonist to benefit bone cells without harming the breast and uterus.²⁹

Bone remodeling is an intricate process that involves osteoblasts, osteoclasts, and osteocytes, and is governed by several intracellular signaling pathways, notably the canonical Wnt/β-catenin pathway. This pathway is essential for the intracellular activities that promote osteoblast maturation and the formation of bone.^30,31 During secondary osteoporosis, disruptions in the Wnt/β-catenin pathway can lead to decreased osteoblast differentiation and activity, alongside increased apoptosis of osteoblasts and osteocytes.³² An in vitro model showed genistein’s capabilities in promoting osteoblast proliferation and differentiation, while also inhibiting the formation and activity of osteoclasts.³³ WNT10b is crucial in the Wnt canonical pathway, essential for promoting osteoblast formation. Genistein significantly increased Wnt10b expression at doses of 10, 50, 100, and 200μM, and enhanced protein and transcription factor levels in primary osteoblasts.³¹ This highlight’s genistein’s potential influence on the Wnt/β-catenin signaling pathway in osteocytes, stimulating Wnt10b, facilitating β-catenin's nuclear translocation, and reducing sclerostin, especially at doses of 200μM.³¹ Sclerostin is a protein found in osteocytes that functions to inhibit the Wnt pathway.^31,34 Its downstream effects include suppressing the production of osteoblasts. By reducing levels of sclerostin, genistein assists in indirectly promoting osteoblast production.³¹

In vitro studies showcased genistein’s ability to inhibit osteoclast activity and induce their apoptosis through intracellular Ca2+ signaling pathways.³⁵ It significantly reduced osteoclast numbers in rat femoral tissues and showed strong inhibition of osteoclast-like cell formation in mouse marrow cultures. Genistein's inhibitory effects on osteoclasts, at 10^-5 M, were equal to that of 17 β-estradiol's (at 10^-8 M). Additionally, its effects were even more potent than other isoflavones and phytoestrogens.^36,37 Genistein may also impact the osteoprotegerin (OPG)-receptor activator of nuclear factor κB ligand (RANKL) system. Changes in this system may underlie various metabolic bone disorders, including osteoporosis, as recent studies have suggested.^38–41 OPG and RANKL are key components involved in regulating bone resorption.^42,43 OPG is a part of the TNF receptor superfamily and is produced by osteoblasts, while RANKL is secreted by cells of the osteoblastic lineage.⁴⁴ OPG acts as a decoy by binding to RANKL, preventing its interaction with RANKL. This binding stops osteoclast formation, activation, and survival, thus promoting bone formation.⁴⁵ Serum levels of RANKL, OPG, and their ratio were assessed in postmenopausal women who were treated with genistein for 24 months. Participants received either genistein (n=198; 54mg/d) or placebo (n=191) and the genistein group showed significantly lower RANKL levels and higher OPG levels compared to placebo, at both 12 and 24 months. By 24 months, genistein also significantly lowered the RANKL/OPG ratio compared to placebo. This reduction in RANKL/OPG ratio may contribute to genistein’s beneficial impact on BMD.^44,45 Genistein is the only known agent to collectively inhibit RANKL, stimulate Wnt-beta-catenin, and inhibit sclerostin.³¹

Bitto A et al²⁵ compared genistein's effectiveness to common treatments like alendronate, raloxifene, and estradiol in ovariectomized rats (Table 3).^46–49 Genistein, at 10mg kg−1, outperformed these treatments in improving BMD and bone mineral content (BMC), demonstrating greater bone-building capabilities than alendronate, the mainstay of postmenopausal osteoporosis treatment. Genistein more effectively increased bone formation markers such as bone-alkaline phosphatase (b-ALP) and decreased bone resorption markers like collagen C-telopeptide (CTX). Histological analyses also indicated increased femoral fracture resistance and enhanced overall bone quality.

TABLE 3.

Osteoporosis treatments

TREATMENTS	HISTOLOGICAL SCORE: BONE QUALITY	FEMORAL BREAKING STRENGTH	SIDE EFFECTS
Estradiol	1.4	113	VTE, stroke, breast cancer, endometrial cancer†
Raloxifene	1.0	115	VTE, hot flashes, arthralgia, insomnia, flu-like symptoms†
Alendronate	0.6	130	Atypical fractures, GI side effects, bone, joint, and muscle pain
Genistein	0.2	132	Nausea, upset stomach*

VTE: Cenous thromboembolism

^†2017 guidelines from the American College of Physicians recommend against using raloxifene or HRT to treat osteoporosis in women

*In clinical trials, women who took genistein and those who took a placebo (calcium and vitamin D) had a similar incidence of stomach upset

Morabito et al⁵⁰ compared the effects of genistein and HRT (composed of estradiol combined with norethisterone acetate) on bone metabolism and BMD in postmenopausal women, finding that both significantly enhanced BMD in the femur and lumbar spine. Genistein's effect on bone resorption was measured through decreased urinary excretion of pyridinoline and deoxypyridinoline, markers of bone resorption. After 6 to 12 months of daily genistein (54mg/day) administration, there was a significant decrease in excretion of these markers.^47,50,51 Marini et al⁴⁷ performed a similar trial that lasted 24 months, using genistein (54mg/day) in combination with vitamins D3 and calcium. Results were comparable and showed genistein’s ability to raise femoral and lumbar spinal BMD, while reducing excretion of bone resorption markers in postmenopausal women.⁴⁷ Additionally, 24 months of genistein treatment, at 54mg/day, did not pose a clinically significant risk to the uterus.^47,50 This reduction in bone loss, and lack of significant consequences to the uterine lining, underscores genistein's potential as an effective treatment for bone loss in postmenopausal women.

Genistein for metabolic issues: fat accumulation and cardiovascular health. Menopause is closely tied to an elevation in body weight, accumulation of visceral fat, and changes in body fat distribution, which can increase the risk of metabolic issues such as insulin resistance, Type 2 diabetes, and hyperlipidemia, which may collectively potentiate cardiovascular issues.⁵² Genistein has been shown to possess cardioprotective effects that help reduce the progression of such complications.

Studies involving ovariectomized mice demonstrated genistein’s effects on dampening numerous postmenopausal metabolic symptoms such as weight gain, elevated build-up of fat, insulin resistance, and worsening lipid profile.^53,54 Genistein may also have promising utility in regulating the proliferation and migration of leptin, a peptide hormone involved in the maintenance of hunger and satiety.⁵⁵ Its potential ability to modulate body fat mobilization through induction of adipose tissue apoptosis can provide another mechanism for mitigating elevations in postmenopausal adiposity.^53,56,57

Genistein's ability to improve lipid profiles plays a crucial role in reducing cardiovascular risk. In ovariectomized rats, it significantly lowered serum cholesterol and triglyceride levels.⁵⁴ Human studies demonstrated that genistein, at 36mg/day, significantly lowers LDL cholesterol and the LDL-HDL ratio.^58,59 The LDL-HDL ratio represents the metric most strongly associated with a higher risk of cardiovascular disease among women.⁶⁰ Additionally, genistein stabilized insulin levels by modifying membrane binding sites and was the only compound in the study that did not increase uterus weight, unlike coumestrol and zearalenone.^61–66 In a randomized, double-blind, placebo-controlled study, 120 postmenopausal women with metabolic syndrome were treated with either 54mg of genistein daily or a placebo, for one year. After one year, those receiving genistein experienced significant reductions in fasting glucose, fasting insulin, and systolic/diastolic blood pressures, while no changes were observed in the placebo group. Genistein recipients also saw statistically significant health improvements, including increased HDL and decreased LDL and triglycerides. There were no significant differences in side effects or discontinuation rates between the genistein and placebo groups.⁶⁷ 54mg/day of genistein demonstrated its potential in comprehensively reducing the risk of developing Type 2 diabetes mellitus, while avoiding major side effects.⁶⁸

Genistein for VMS. VMS can include hot flashes which are characterized by sudden intense heat, sweating, and flushing, and often linked to hormonal shifts such as estrogen deficiency. Postmenopausal Asian women have low VMS prevalence, possibly due to their high soy diet. While estrogen supplementation is effective in treating these symptoms, it poses risks.²⁰ A study administering 54mg/day of genistein for 12 months showed significant reductions in daily hot flashes by 22 percent, 29 percent, and 24 percent after three, six, and 12 months, respectively.⁶⁹ D'Anna et al²⁰ strengthened these results in a larger study (n=389), noting a nearly 60-percent reduction in hot flashes at the study’s conclusion, without significant endometrial lining changes, highlighting genistein’s efficacy without the adverse effects associated with estrogen supplementation.

Genistein: skin effects. Menopause plays a substantial role in aging of the skin. Skin thinning, fragility, laxity, and delayed wound healing are all potential sequelae of ovarian failure and a subsequent decline in estrogen. Genistein has shown promise in treating these symptoms in addition to functioning as a protective factor against UV radiation and skin cancer. Due to its anti-inflammatory, anti-tumor, and estrogen-like effects, genistein can be useful in improving the quality, appearance, and health of the skin.

Genistein for UV protection. Exposure to ultraviolet (UV) rays, particularly UVB (280–320nm), can cause oxidative damage, leading to premature skin aging, sunburn, and skin cancer.^70,71 UV exposure results in epidermal DNA damage, triggering an inflammatory response marked by erythema, swelling, and increased cell proliferation, which can indicate the risk of photocarcinogenesis. This response is mediated by histamine and pro-inflammatory prostaglandins, and is reliant on oxygen radicals, making it vulnerable to antioxidant intervention.⁷² Topical antioxidants are effective in protecting skin from UV-induced oxidative damage and have anti-inflammatory properties that help address issues like photoaging and potentially skin cancer.^3,73

Research has shown that genistein can reduce free radicals involved in skin aging and may protect against oxidative stress from UVB radiation.⁷⁰ In mice, dietary genistein (250ppm) significantly boosts the production of endogenous antioxidants like superoxide dismutase (SOD) and various forms of glutathione, particularly impacting the small intestine and skin.⁷⁴ These antioxidants help maintain balanced reactive oxygen species (ROS) levels and mitigate cellular stress. An imbalance, with a higher oxidant/antioxidant ratio, can elevate ROS levels, causing oxidative stress that may damage DNA, proteins, and lipids, leading to premature aging.⁷⁵

Nitric oxide (NO) is implicated in photoaging and plays a role in various inflammatory skin conditions, making it a target for treatment.^76–78 It has been noted that the inducible nitric oxide synthase (iNOS) isoform produces excess NO in response to UV light exposure.⁷⁹ Genistein has been shown to reduce endothelial NOS (eNOS) and iNOS expression dose-dependently in cells pre-treated with hydrogen peroxide.⁸⁰ Additionally, genistein effectively inhibits prostaglandin production in human cell cultures and skin, both under normal and UV-induced conditions, comparable to the antioxidant N-acetylcysteine. This supports the role of ROS in mediating UV radiation's effects, such as sunburn and immunosuppression.⁸¹

When administered before UV exposure, genistein (15mmol/L) inhibited the UV-induced rise in cyclooxygenase-2 (COX-2) expression in human keratinocyte cultures, suggesting anti-inflammatory properties.^81,82 Additionally, 60 μM of genistein significantly reduced COX-2 and increased expression of the Gadd45 gene in UVB-irradiated BJ-5ta cells (human skin fibroblast cells preserved with human telomerase reverse transcriptase (hTERT)), which is known to activate in stressful conditions, such as ionizing radiation.⁸³ Gadd45 is crucial for cell repair, acting as a stress sensor and influencing cell cycle arrest, DNA repair, and cell fate (survival or apoptosis).^83–85 This evidence supports genistein's potential as a protective agent against photodamage.

Genistein for skin cancer prevention.Skin cancer is the most common cancer globally. It is categorized into two main types: cutaneous melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The development of skin cancer is influenced by various factors, such as ultraviolet radiation, tanning beds, genetic factors, and organ transplantation.^86,87 Studies have proposed genistein as a promising candidate for skin cancer therapy, due to its antitumor, chemopreventative, and anti-inflammatory capabilities.^86,88,89

Genistein appears to inhibit DNA helicase and topoisomerase I and II, enzymes essential for DNA replication, and can arrest the cell cycle and induce apoptosis at critical points like G1 to S and G2 to M, reducing cell growth.^90,91 It is shown to also reduce tumor angiogenesis by inhibiting vascular endothelial growth and promoting breakdown of extracellular matrix (ECM) proteins.^92,93 As a tyrosine kinase inhibitor, genistein may limit cancer cell proliferation and has anti-inflammatory properties that enhance lymphocyte immunostimulatory effects.^92,94 It boosts both non-specific and humoral immunity, thereby enhancing immune responses, and stimulates interleukin production, supporting its role in cancer chemoprevention.^90,92,95

Cyclin D1, a nuclear protein encoded by the CCND1 gene, is vital for cell growth and tumor cell survival.^96,97 It facilitates the transition from the G1 to S phase of the cell cycle and is often overexpressed in melanoma, enhancing tumor progression and proliferation due to abnormal degradation that increases its stability.^97–99 Reductions in p-16 and/or p-21 proteins can trigger melanoma by failing to effectively block Cyclin D1 activity.¹⁰⁰ Genistein has been shown to reduce Cyclin D1 levels, leading to an arrest of the G2/M phase. In melanoma cells, low doses (25 and 50μM) of genistein increased Cyclin D1 expression, while higher doses (100μM) decreased it, leading to reduced cell growth and increased apoptosis.⁹⁷

Studies showed that T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK), a serine-threonine kinase, is crucial in skin cancer development. Both phosphorylated and total levels of TOPK are significantly higher in human actinic keratosis (AK) and cutaneous SCC, compared to normal skin.^88,101 This may suggest that inhibiting TOPK could be an effective strategy for treating skin cancer. Roh et al⁸⁸ investigated the therapeutic effects of a genistein derivative, in a 1% topical formulation, on SCC caused by chronic solar-simulated light (SSL).⁸⁸ In mouse models, early treatment significantly reduced chronic SSL-induced SCC development and demonstrated therapeutic potential by effectively reducing tumor regrowth post-treatment.^88,102

Genistein for wound healing and aberrant scar prevention. Perimenopausal and postmenopausal estrogen deficiency can cause skin atrophy, increased dryness, reduced collagen and water content, diminished sebaceous secretion, and loss of elasticity. These changes are believed to impair wound healing.¹ Delays in wound healing with age have also been linked to several other factors including reduced levels of transforming growth factor-beta1 (TGF-β1) and vascular endothelial growth factor (VEGF), reduced collagen production, and increased elastase concentration.^103–105 Studies have indicated that genistein may play a beneficial role in this process by modulating TGF-β1 secretion from dermal fibroblasts, enhancing healing.^103,106,107

In addition to TGF-β1 secretion, fibroblasts also induce collagen production which is vital for wound repair. Genistein’s impact on collagen production was assessed in human dermal fibroblasts undergoing oxidative stress induced by t-butylhydroperoxide (t-BHP). t-BHP’s inhibitory effects on collagen production were counteracted at 1μM genistein, demonstrating a protective effect. The findings indicate that at dietary levels (1μM), genistein protects human dermal fibroblasts against the reduction in collagen production triggered by oxidative stress.¹⁰⁸

To further assess genistein's impact on wound healing, mice were given a standard diet (control group) or one enriched with genistein at either 0.025% or 0.1%. After inducing skin wounds, daily measurements showed that the control group's wounds reduced in size by 20 percent within three days. In contrast, the 0.1% genistein group saw a 50 percent wound size reduction in the same timeframe, significantly outperforming the control. Although the 0.025% genistein group initially showed a notable reduction on day one, its effects didn't significantly differ from the control thereafter. This indicates that a higher dose of genistein (0.1%) accelerates wound healing more effectively, suggesting a dose-dependent relationship.¹⁰⁹

Ovariectomy hastens the aging process in skin, given that sufficient levels of estrogen are necessary to maintain the skin's structural integrity and functional abilities. In skin samples from untreated ovariectomized rats, there was a reduction in TGF-β1, VEGF, MMP-2 and MMP-9, and TIMP-1 and TIMP-2, compared to control.^110,111 In a study where ovariectomized rats were treated with genistein for six months (at doses of 1 and 10mg/kg/day via subcutaneous injections), full-thickness incisional wounds were created to assess healing at 7 and 14 days. Genistein effectively improved wound healing by enhancing the remodeling and turnover of the ECM in these rats. Notably, at both 7- and 14-days post-incision, 1mg/kg genistein demonstrated greater efficacy in enhancing various skin healing parameters compared to estradiol or raloxifene.¹¹¹

The abnormal wound and scar tissue microenvironment, characterized by increased growth factors, drives fibroblast changes and scar progression, leading to hypertrophic scars or keloids. Many of these growth factors utilize the tyrosine protein kinase (TPK) pathway to enhance cell growth, development, and differentiation.^112–117 Genistein, which may function as a TPK inhibitor, was used to evaluate its effects on inhibiting cultured human hypertrophic scar fibroblast (HSFB) proliferation and TPK signal transduction. Significant differences were observed in both the 50μmol/l and 100μmol/l treatment groups compared to the control group at all time points (p<0.01), demonstrating a dose- and time-dependent relationship on HSFB proliferation. HSFB growth and proliferation, collagen synthesis, type I or III pre-collagen mRNA expression, and intracellular TPK activity were significantly decreased at the 50μmol/l or 100μmol/l concentrations of genistein.¹¹⁸

Keloids arise from excessive connective tissue growth during abnormal wound healing, characterized by an imbalance between profibrotic and antifibrotic cytokines that manage ECM synthesis and remodeling.¹¹⁹ Central to this process are TGFβ isoforms and connective tissue growth factor (CTGF). TGFβ1 primarily promotes ECM synthesis and contraction, while CTGF extends collagen deposition, further perpetuating fibrosis. Platelet derived growth factor (PDGF) also plays a role in this process as it is mitogenic and chemotactic for connective tissue cells and stimulates collagenase production and synthesis of ECM components, such as fibronectin and hyaluronic acid. There are several other mediators that play a role in keloid development through facilitating increased fibroblast proliferation, apoptosis resistance, and inflammation. Other growth factors and cytokines such as insulin-like growth factor-2 (IGF-2) and prostaglandin E2 (PGE2), as well as key genes such as the tumor suppressor p53, cyclin-dependent kinase inhibitor CDKN1A (p21), and BCL2 family genes have all been implicated.^120–124 In vitro, genistein exerted antifibrotic effects through suppression of CTGF mRNA and protein levels, modulation of p53, p21, and BCL2 family gene expression, all in a dose-dependent manner. Genistein, at 370µM, showed the greatest level of CTGF mRNA suppression.¹⁰⁷

Genistein for skin aging, body fat, and aesthetics. The skin and body undergo noticeable changes with aging, especially after menopause due to their heavy dependence on estrogen. As menopause shifts body fat to the abdomen, thighs, and buttocks, wrinkles are potentiated through diminished supportive facial fat, effectively accelerating skin aging.³

Wrinkles, however, although influenced by environmental and hormonal factors, are ultimately caused by a reduction in skin elasticity, stemming from the degeneration of elastic fibers and the loss of connective tissue through the accumulation of collagen degradation products.¹²⁵ During aging, changes occur in two types of collagen: type I, the main collagen in adult skin, and type III, which is found throughout the body.¹²⁶ A decrease in both collagen types and in the type III/I ratio within the dermis occurs with aging. Estrogen deficiency can lead to a reduction in collagen by two percent, a reduction in skin elasticity by 1.5 percent, and a reduction in skin thickness by approximately 1.13 percent annually after menopause.^126,127 The first five years post-menopause however can see up to a 30-percent reduction in type I and III skin collagen, a trend that mirrors the bone mass decline found in postmenopausal women. This reduction in collagen content and skin thickness is more closely linked to estrogen deficiency than to chronological aging.¹²⁸

Promising outcomes were demonstrated by genistein when tested in anti-aging cosmetic products. These involve improving skin elasticity, reducing photoaging, and mitigating the development of skin cancer. Creams infused with genistein have been effective in reducing wrinkles and improving skin dryness.¹²⁹ Genistein’s ability to induce subcutaneous VEGF production and enhance TGF-β levels in the skin creates downstream effects that increase skin collagen thickness. Additionally, genistein counteracts matrix metalloproteinases (MMPs) by elevating tissue inhibitors of metalloproteinases (TIMP) protein levels, thereby reducing breakdown of collagen. Consequently, genistein may significantly improve collagen thickness and slow the skin aging process.^110,126

A topical anti-aging formulation (GEN), featuring genistein, vitamin E, vitamin B3, and ceramide, was developed to counteract menopausal skin effects. In a randomized, controlled trial with 50 postmenopausal women, 25 received the GEN product and 25 a placebo cream, applied twice daily for six weeks. Results indicated that the GEN product significantly improved skin hydration, reduced the appearance of pores, and diminished several wrinkling metrics compared to the placebo. This suggests that genistein could be effective in improving skin health and appearance in postmenopausal women.¹³⁰ Additionally, a double-blind study with 26 middle-aged women tested the effects of genistein aglycone. Participants received either 40 mg of genistein aglycone daily or a placebo. The treatment group showed significant improvements in fine wrinkles and cheek skin elasticity after 12 weeks, further supporting the benefits of genistein for skin health and appearance.¹³¹

Genistein in males. Prostate cancer accounts for 15 percent of all cancer diagnoses in men. The incidence of prostate cancer is lower in Asian countries, however, where soy intake is also higher. It has been observed that genistein accumulates in prostatic tissue and may be protective against the development of prostate cancer. One mouse model highlighted genistein’s protective effects against the development of prostate cancer. Mice were provided three different diets: control, low-dose genistein (300mg/kg), and high-dose genistein (750mg/kg) and results of prostate cancer incidence were 70 percent, 47 percent, and 32 percent, respectively.¹³² This indicated the possibility that higher dosages of genistein can reduce the risk of prostate cancer development. A recent meta-analysis supports previous studies showing that soy intake, and genistein intake specifically, are associated with a decreased risk of prostate cancer growth and development (p<0.001 and p=0.008, respectively).¹³³ A case-control study in Japanese men looked at isoflavone consumption and assessed its association with prostate cancer risk. Individuals consuming the most genistein (≥2.5mg/day) versus the least (<1.1mg/day) had an odds ratio (OR) of 0.42, demonstrating a significant linear trend (P<0.05).¹³⁴ Additionally, another study assessed 100 Chinese men for prostate cancer and diagnosed 46 of them with prostate cancer. The median plasma concentration of genistein in patients without prostate cancer (728.6ng/mL) was significantly higher compared to those with prostate cancer (513.0ng/mL) (P<0.05). That study’s multivariate analysis showed plasma genistein’s potential impact, alongside age and smoking history, in determining risk of prostate cancer.¹³⁵ As the second most common cancer worldwide, it is crucial to identify potentially modifiable factors in the development of prostate cancer, and these results show promise n genistein’s utility as a preventative agent.

Nonetheless, as a phytoestrogen, it may be possible that genistein intake also has potentially deleterious effects on the reproductive health of males. A study on adult male rats exposed to genistein in utero, demonstrated a dose-dependent relationship between genistein and its negative impact on fertility. Epidydimal sperm counts were significantly lower in the 20mg and 100mg groups, compared to control. Sperm counts in the 2mg group were not significantly different from control. Additionally, motile and viable sperm percentages were significantly reduced in the 100mg group compared to controls. The 2mg and 20mg groups did not seem to significantly impact motility and viability.¹³⁶ Shi et al¹³⁷ tested genistein’s impact on fertility in male mice by providing a low-dose (40mg/kg) and high-dose (800mg/kg) genistein diet. The low-dose diet demonstrated improved testes weight, seminiferous tubule diameter, serum testosterone levels, and spermatogenesis. Conversely, the high-dose diet significantly reduced body weight, testes weight, and testes size. This was strengthened by another study showing that high-dose (300mg/kg genistein) can negatively impact antral follicular growth in mice.¹³⁸ Interestingly, one mouse study demonstrated an improvement in fertility when treated with genistein, although a dose-response relationship was not found. Intraperitoneal administration of genistein occurred at varying dosages: 1, 2, and 4mg/kg. Administration of genistein significantly enhanced sperm count, motility, and viability. It also improved testosterone, LH, and FSH levels.¹³⁹ These findings show the potentially detrimental effects of genistein exposure on the male reproductive system, particularly when exposure occurs in utero, but are likely attributed to the very high doses of genistein. Additionally, the studies included were performed on mice and rats with doses significantly higher than human consumption levels.¹⁴⁰

DISCUSSION

The sex hormone estrogen is critically involved in the regulation of key biological processes across the entire body, and a chronic estrogen deficiency or imbalance is associated with an increased risk for the development of various pathologies, such as dyslipidemia, cardiovascular disease, VMS, osteoporosis, xerosis, dermal atrophy, poor wound healing, and cancer. Following menopause, women enter a state of chronic estrogen deficiency and may experience a decline in quality of life because of the associated symptoms and/or disease states. Some of the health risks of estrogen deficiency may be mitigated by restoring a portion of normal estrogen activity, which is conventionally accomplished with estrogen supplementation. However, the risks associated with estrogen supplementation, such as VTE and cancer, may contraindicate therapy or otherwise deter patients from pursuing treatment. An alternative therapeutic solution with a better risk profile would enable more patients to pursue and achieve symptomatic relief and forestall the development of estrogen osteoporotic women treated orally with genistein. Moreover, genistein outperforms alendronate and raloxifene in its ability to reduce osteoclastic markers.²⁵ Its selective binding to ER-β, strongly expressed in human bone, particularly trabecular bone, underscores its role in bone formation and potential as a selective ER-β agonist for osteoporosis treatment.^16,27,29,142

Genistein has shown significant anti-inflammatory effects and enhanced DNA repair.⁸³ This aligns with recent research displaying genistein's anti-inflammatory and anticarcinogenic properties, including its ability to modulate COX-2 in various cellular systems and prevent UV-induced DNA damage in skin models. As UV damage is also a risk factor for skin cancer development, genistein’s anti-tumor properties may also play a role in reducing its incidence, a valuable function given the prevalence of skin cancer worldwide. A genistein derivative was found to reduce tumor growth and oncogenic expression, and a topical application of this derivative was protective against tumor regrowth.⁸⁸ Genistein has also been found to promote cell growth at lower doses and induce apoptosis at higher doses, highlighting its potential as a therapeutic agent for malignant melanoma at appropriate dosages.⁹⁷ The findings of studies investigating genistein and its derivatives further underscore its potential as a therapeutic agent, offering avenues for targeted interventions in skin cancer treatment.

Estrogen depletion during menopause contributes to skin atrophy, diminished collagen production, and impaired wound healing. However, genistein shows promise as an agent capable of ameliorating these effects. Genistein has demonstrated antioxidant properties through mitigation of the effects of oxidative stress and downregulation of proinflammatory mediators, by which it contributes to improved wound healing.¹⁰⁹ Additionally, genistein shows promise in inhibiting hypertrophic scar fibroblast proliferation and modulating key genes implicated in keloid development.¹⁰⁷ The topical application and oral administration of genistein was shown to alleviate skin aging, reduce fine wrinkles, and improve skin elasticity.^130,131 These findings collectively underscore genistein's multifaceted mechanisms in promoting skin health and wound healing, suggesting its therapeutic utility in mitigating the effects of estrogen deficiency, including aberrant wound healing processes and aging skin.

Limitations. The studies on genistein show very significant promise however, one of the main limitations is that since genistein is not a drug, individual studies are using different sources as well as different amounts of genistein. Unless reproducible medical food grade sourcing is used, different studies cannot necessarily be correlated to each other. There is also little data on the use of genistein in women taking hormonal supplements during menopause. Further studies should be conducted on this population with medical food grade dosing. Overall, future research should prioritize larger, long-term clinical trials with standardized dosages, and assess efficacy and side effects in diverse populations to further establish genistein’s role in clinical practice.

CONCLUSION

Genistein functions as a SERM and offers various health benefits, particularly for postmenopausal women. By mimicking estrogen, it can alleviate menopausal symptoms and conditions. This is strengthened by the availability of medical foods that improves upon genistein’s bioavailability and therapeutic efficacy in mitigating the downstream effects of estrogen deficiency. Genistein aids in metabolic and cardiovascular health and is a potential alternative for estrogen supplementation, reducing the risks of obesity, diabetes, and cardiovascular disease. Furthermore, it benefits bone health by increasing density and lowering resorption, offering a safer osteoporosis treatment. It also promotes skin health by enhancing elasticity, reducing wrinkles, and improving wound healing, through collagen and elastin production, while also providing protection against UV damage and skin cancer. Genistein's therapeutic potential makes it a valuable supplement for postmenopausal women and may even support prostate cancer prevention in men.