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Edwin D Lephart,1 Frederick Naftolin2 1Department of Cell Biology, Physiology and The Neuroscience Center, Brigham Young University, Provo, UT, USA; 2Department of Research and Development, e-Bio Corporation, Woodbridge, CT, USACorrespondence: Edwin D Lephart, Department of Cell Biology, Physiology and The Neuroscience Center, LS 4005, College of Life Sciences, Brigham Young University, Provo, UT, 84602, USA, Tel +801 422-2006 ; +801 319 8173, Fax +1 801 422 0700, Email Edwin_Lephart@byu.eduAbstract: The narrative for this overview focuses on updating the factors that influence skin aging and the important role estrogens and selective estrogen receptor modulators (SERMs) play in this process (mainly utilizing journal reports and reviews from the last four years). Estrogens have been known and studied for over a century. For many years, it has been recognized that estrogens are important in the maintenance of human skin. Women seek cosmetic and medical treatments to improve dermal health and physical characteristics to enhance their self-perception and inhibit skin aging, particularly in highly visible body areas. The goal: to retain estrogen’s positive benefits while aging and especially at/after menopause where estrogen-deficient skin contributes to the dramatic decline in skin health. In this overview, both background information and recent novel findings are included that cover aging (general mechanisms), skin aging, and factors that influence skin aging (intrinsic, extrinsic, skin microbiome and gut microbiome.) Plus, estrogen’s general role in maintaining skin health is presented through the classical estrogen receptors alpha (α) and beta (β) and non-classical (or non-genomic) estrogen receptor (G protein-coupled seven transmembrane receptor). More importantly, the various benefits of 17β-estradiol in skin health are examined (ie, skin collagen and elastin profiles that follow 17β-estradiol levels during aging and at/after menopause). Finally, a revision of information for estrogenic skin topical applications involving isoflavonoid compounds that act as SERMs, but are classified as endocrine disruptors, and a topical estrogen analog are explored to update the known and unknown characteristics of these treatments. Further study is warranted to understand the biological and molecular mechanisms by which estrogens support and enhance dermal health and wellbeing.Keywords: estrogens, skin aging, estrogen receptors, SERMs, isoflavonoid, microbiome

BACKGROUND: The discovery of equol in human urine more than 2 decades ago and the finding that it is bacterially derived from daidzin, an isoflavone abundant in soy foods, led to the current nutritional interest in soy foods. Equol, unlike the soy isoflavones daidzein or genistein, has a chiral center and therefore can occur as 2 distinct diastereoisomers. OBJECTIVE: Because it was unclear which enantiomer was present in humans, our objectives were to characterize the exact structure of equol, to examine whether the S- and R-equol enantiomers are bioavailable, and to ascertain whether the differences in their conformational structure translate to significant differences in affinity for estrogen receptors. DESIGN: With the use of chiral-phase HPLC and mass spectrometry, equol was isolated from human urine and plasma, and its enantiomeric structure was defined. Human fecal flora were cultured in vitro and incubated with daidzein to ascertain the stereospecificity of the bacterial production of equol. The pharmacokinetics of S- and R- equol were determined in 3 healthy adults after single-bolus oral administration of both enantiomers, and the affinity of each equol enantiomer for estrogen receptors was measured. RESULTS: Our studies definitively establish S-equol as the exclusive product of human intestinal bacterial synthesis from soy isoflavones and also show that both enantiomers are bioavailable. S-equol has a high affinity for estrogen receptor beta (K(i) = 0.73 nmol/L), whereas R-equol is relatively inactive. CONCLUSIONS: Humans have acquired an ability to exclusively synthesize S-equol from the precursor soy isoflavone daidzein, and it is significant that, unlike R-equol, this enantiomer has a relatively high affinity for estrogen receptor beta. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Abstract Background Soy-derived isoflavones potentially protect against obesity and depression. In five different studies we examined the influence of soy-containing diets or equol injections on depression, serotonin levels, body weight gain (BW) and white adipose tissue (WAT) deposition in female Long-Evans rats at various stages of life [rats were intact, ovariectomized or experienced natural ovarian failure (NOF)]. Results In general, animals fed a soy-rich diet (Phyto-600) and/or administered equol (@ 5 mg/kg/day) displayed significant decreases in BW and WAT compared to a low-soy diet. When equol was injected alone (5 mg/kg/day), experiments 1, 4, and 5 demonstrated that body weight was significantly decreased. Equol has body weight control effects in females that are dependent on ovarian status and/or age of diet initiation. Experiments 1-4 all displayed no significant differences in depressive-related behavior as measured by the Prosolt forced swim test (PFST) when soy-rich (Phyto-600) or low-soy diets (Phyto-low) or equol treatments (5 mg/kg/day) were tested in female rats at various ages or hormonal status. Results of all the experiments are not presented here due to space limitations, but data from experiment 5 are presented. From conception female rats were exposed to either: a) a soy-rich (Phyto-600) or b) low-soy diet (Phyto-low). After 290 days all rats experienced NOF. At 330 days-old the animals were examined in the Porsolt forced swim test (PFST). One month later a second PFST was performed [after Phyto-low fed animals were injected with equol (5 mg/kg/day) for one week prior to the second PFST]. At the first PFST, serotonin and mobility levels were significantly decreased in the Phyto-low fed animals compared to animals that consumed the Phyto-600 diet. After equol injections at the second PFST, mobility and serotonin levels significantly increased in aged NOF rats fed the Phyto-low diet (to levels comparable to Phyto-600 fed animals). Conclusions Consumption of dietary isoflavones or equol exposure in rats has body weight controlling effects and equol specifically may have antidepressant potential dependent upon diet initiation and/or dosage of treatments. The current study demonstrates that equol is able to decrease body weight, abdominal WAT, and depressive-related behavior. While other factors and mechanisms may play a role, in part, the present results provide a greater understanding of how isoflavonoid molecules modulate the brain's influence on behavior.

Abstract Background To determine: in vitro binding affinity of equol for 5alpha-dihydrotestosterone (5alpha-DHT), in vitro effects of equol treatment in human prostate cancer (LNCap) cells, and in vivo effects of equol on rat prostate weight and circulating levels of sex steroid hormones. Methods First, in vitro equol binding affinity for 5alpha-DHT was determined using 14C5alpha-DHT combined with cold 5alpha-DHT (3.0 nM in all samples). These steroids were incubated with increasing concentrations of equol (0-2,000 nM) and analyzed by Sephadex LH-20 column chromatography. 14C5alpha-DHT peak/profiles were determined by scintillation counting of column fractions. Using the 14C5alpha-DHT peak (0 nM equol) as a reference standard, a binding curve was generated by quantifying shifts in the 14C5alpha-DHT peaks as equol concentrations increased. Second, equol's in vitro effects on LNCap cells were determined by culturing cells (48 hours) in the presence of increasing concentrations of dimethyl sulfoxide (DMSO) (vehicle-control), 5alpha-DHT, equol or 5alpha-DHT+equol. Following culture, prostate specific antigen (PSA) levels were quantified via ELISA. Finally, the in vivo effects of equol were tested in sixteen male Long-Evans rats fed a low isoflavone diet. From 190-215 days, animals received 0.1cc s.c. injections of either DMSO-control vehicle (n = 8) or 1.0 mg/kg (body weight) of equol (in DMSO) (n = 8). At 215 days, body and prostate weights were recorded, trunk blood was collected and serum assayed for luteinizing hormone (LH), 5alpha-DHT, testosterone and 17beta-estradiol levels. Results Maximum and half maximal equol binding to 5alpha-DHT occurred at approximately 100 nM and 4.8 nM respectively. LNCap cells cultured in the presence of 5alpha-DHT significantly increased PSA levels. However, in the presence of 5alpha-DHT+equol, equol blocked the significant increases in PSA levels from LNCap cells. In vivo equol treatment significantly decreased rat prostate weights and serum 5alpha-DHT levels but did not alter LH, testosterone, and estradiol levels. Conclusions Equol administration appears to have potential beneficial effects for prostate health and other 5alpha-DHT mediated disorders. Equol administration: reduces PSA levels from LNCap cells under 5alpha-DHT stimulation, decreases rat prostate size, decreases serum 5alpha-DHT levels and androgen hormone action, while not altering other circulating sex steroids or LH levels.

Abstract Background High dietary intake of selenium or soybean isoflavones reduces prostate cancer risk. These components each affect androgen-regulated gene expression. The objective of this work was to determine the combined effects of selenium and isoflavones on androgen-regulated gene expression in rat prostate. Methods Male Noble rats were exposed from conception until 200 days of age to diets containing an adequate (0.33-0.45 mg/kg diet) or high (3.33-3.45 mg/kg) concentration of selenium as Se-methylselenocysteine and a low (10 mg/kg) or high (600 mg/kg) level of isoflavones in a 2 × 2 factorial design. Gene expression in the dorsolateral prostate was determined for the androgen receptor, for androgen-regulated genes, and for Akr1c9, whose product catalyzes the reduction of dihydrotestosterone to 5alpha-androstane-3alpha, 17beta-diol. Activity of hepatic glutathione peroxidise 1 and of prostatic 5alpha reductase were also assayed. Results There were no differences due to diet in activity of liver glutathione peroxidase activity. Total activity of 5alpha reductase in prostate was significantly lower (p = 0.007) in rats fed high selenium/high isoflavones than in rats consuming adequate selenium/low isoflavones. High selenium intake reduced expression of the androgen receptor, Dhcr24 (24-dehydrocholesterol reductase), and Abcc4 (ATP-binding cassette sub-family C member 4). High isoflavone intake decreased expression of Facl3 (fatty acid CoA ligase 3), Gucy1a3 (guanylate cyclase alpha 3), and Akr1c9. For Abcc4 the combination of high selenium/high isoflavones had a greater inhibitory effect than either treatment alone. The effects of selenium on gene expression were always in the direction of chemoprevention Conclusion These results suggest that combined intake of high selenium and high isoflavones may achieve a greater chemopreventive effect than either compound supplemented individually.

Abstract Background High dietary intake of selenium or isoflavones reduces risk factors for prostate cancer. We tested whether combined supplementation of these two dietary components would reduce prostate cancer risk factors in rats more than supplementation of each component individually. Methods Male Noble rat pups were exposed from conception to diets containing an adequate (0.33–0.45 mg/kg diet) or high (3.33–3.45 mg/kg) concentration of selenium as Se-methylselenocysteine and a low (10 mg/kg) or high (600 mg/kg) level of isoflavones in a 2 × 2 factorial design. Pups consumed their respective diets until sacrifice at 35, 100, or 200 days. Male Noble rat breeders, whose exposure to the diets began after puberty, were sacrificed at 336 days. Rats were weighed biweekly. Blood was collected at the time of sacrifice and body fat and prostates were dissected and weighed. Serum levels of leptin, IGF-1, and testosterone were determined using ELISA kits. Serum levels of isoflavones were assayed by GC/MS. Liver activity of selenium-dependent glutathione peroxidase 1 was measured as an indicator of selenium status. Results Serum isoflavone concentrations were nearly 100-fold higher at 35 days of age (1187.1 vs. 14.4 ng/mL, mean ± SD) in pups fed the high vs. low isoflavone diets, and remained so at 100 and 200 days, and in breeders. There were no dietary differences in liver glutathione peroxidase activity in pups or breeders. High isoflavone intake significantly (p = 0.001–0.047) reduced body weight in rat pups from 35 days onward, but not in breeders. Body fat and leptin were likewise significantly reduced by high isoflavones in pups while effects in breeders were less pronounced but still significant. High intake of Se and isoflavones each decreased serum IGF-1 in pups at 100 and 200 days, but not in breeders. No consistent dietary effects were observed on serum testosterone or relative weights of prostates. In pups, the combination of high isoflavones and high selenium produced the lowest weight gain, the lowest serum leptin, and the lowest serum IGF-1 concentrations of all four diets. Conclusion Combined intake of high selenium and high isoflavones may achieve greater chemopreventive effects than either compound individually. The timing of supplementation may determine the significance of its effects.

Abstract Background Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. It is known that 17beta-estradiol induces apoptosis in anteroventral periventricular nucleus (AVPV) in rat brain. Also, there is evidence that consumption of soy isoflavones reduces the volume of AVPV in male rats. Therefore, in this study, we examined the influence of dietary soy isoflavones on apoptosis in AVPV of 150 day-old male rats fed either a soy isoflavone-free diet (Phyto-free) or a soy isoflavone-rich diet (Phyto-600). Results The occurrence of apoptosis in AVPV was examined by TUNEL staining. The incidence of apoptosis was about 10 times higher in the Phyto-600 group (33.1 ± 1.7%) than in the Phyto-free group (3.6 ± 1.0%). Furthermore, these apoptotic cells were identified as neurons by dual immunofluorescent staining of GFAP and NeuN as markers of astrocytes and neurons, respectively. Then the dopaminergic neurons in AVPV were detected by immunohistochemistry staining of tyrosine hydroxylase (TH). No significant difference in the number of TH neurons was observed between the diet treatment groups. When estrogen receptor (ER) alpha and beta were examined by immunohistochemistry, we observed a 22% reduction of ERbeta-positive cell numbers in AVPV with consumption of soy isoflavones, whereas no significant change in ERalpha-positive cell numbers was detected. Furthermore, almost all the apoptotic cells were ERbeta-immunoreactive (ir), but not ERalpha-ir. Last, subcutaneous injections of equol (a major isoflavone metabolite) that accounts for approximately 70–90% of the total circulating plasma isoflavone levels did not alter the volume of AVPV in adult male rats. Conclusion In summary, these findings provide direct evidence that consumption of soy isoflavones, but not the exposure to equol, influences the loss of ERbeta-containing neurons in male AVPV.

Abstract Background Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. Few studies have examined the nociception and stress hormone responses after consumption of soy isoflavones. Methods In this study, ovariectomized (OVX) female Long-Evans rats were fed either an isoflavone-rich diet (Phyto-600) or an isoflavone-free diet (Phyto-free). We examined the effects of soy isoflavones on metabolism by measuring body weights, food/water intake, adipose tissue weights as well as serum leptin levels. Also, circulating isoflavone levels were quantified. During chemically induced estrous, nociceptive thresholds were recorded. Then, the animals were subjected to a stressor and stress hormone levels were quantified. Results Body weights were significantly lower in Phyto-600 fed rats compared to Phyto-free values within one week and during long-term consumption of soy isoflavones. Correspondingly, Phyto-600 fed animals displayed significantly less adipose deposition and lower serum leptin levels than Phyto-free values. However, rats on the Phyto-600 diet displayed greater food/water intake compared to Phyto-free levels. No changes in thermal pain threshold or stress hormone levels (ACTH and corticosterone) were observed after activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. Conclusion In summary, these data show that consumption of soy isoflavones 1) increases metabolism, demonstrated by significantly decreased body weights, adipose tissue deposition and leptin levels, but 2) does not alter nociception or stress hormone responses, as indexed by thermal pain threshold, serum corticosterone and ACTH levels in chemically-induced estrous OVX rats.

Abstract Background Phytoestrogens derived from soy foods (or isoflavones) have received prevalent usage due to their 'health benefits' of decreasing: a) age-related diseases, b) hormone-dependent cancers and c) postmenopausal symptoms. However, little is known about the influence of dietary phytoestrogens on regulatory behaviors, such as food and water intake, metabolic hormones and neuroendocrine parameters. This study examined important hormonal and metabolic health issues by testing the hypotheses that dietary soy-derived isoflavones influence: 1) body weight and adipose deposition, 2) food and water intake, 3) metabolic hormones (i.e., leptin, insulin, T3 and glucose levels), 4) brain neuropeptide Y (NPY) levels, 5) heat production [in brown adipose tissue (BAT) quantifying uncoupling protein (UCP-1) mRNA levels] and 6) core body temperature. Methods This was accomplished by conducting longitudinal studies where male Long-Evans rats were exposed (from conception to time of testing or tissue collection) to a diet rich in isoflavones (at 600 micrograms/gram of diet or 600 ppm) vs. a diet low in isoflavones (at approximately 10–15 micrograms/gram of diet or 10–15 ppm). Body, white adipose tissue and food intake were measured in grams and water intake in milliliters. The hormones (leptin, insulin, T3, glucose and NPY) were quantified by radioimmunoassays (RIA). BAT UCP-1 mRNA levels were quantified by PCR and polyacrylamide gel electrophoresis while core body temperatures were recorded by radio telemetry. The data were tested by analysis of variance (ANOVA) (or where appropriate by repeated measures). Results Body and adipose tissue weights were decreased in Phyto-600 vs. Phyto-free fed rats. Food and water intake was greater in Phyto-600 animals, that displayed higher hypothalamic (NPY) concentrations, but lower plasma leptin and insulin levels, vs. Phyto-free fed males. Higher thyroid levels (and a tendency for higher glucose levels) and increased uncoupling protein (UCP-1) mRNA levels in brown adipose tissue (BAT) were seen in Phyto-600 fed males. However, decreased core body temperature was recorded in these same animals compared to Phyto-free fed animals. Conclusions This study demonstrates that consumption of a soy-based (isoflavone-rich) diet, significantly alters several parameters involved in maintaining body homeostatic balance, energy expenditure, feeding behavior, hormonal, metabolic and neuroendocrine function in male rats.

Abstract Background It is well established that the growth of the prostate gland is a hormone-dependent phenomenon involving both androgenic and estrogenic control. Proliferation of prostate cells is, at least in part, under control of estrogen receptor beta (ER-beta). Phytoestrogens bind ER-beta with high affinity and therefore may have antiproliferative effects in the prostate. Methods The prostates of male Long-Evans rats fed a diet high in phytoestrogens (Phyto-600) or very low levels of phytoestrogens (Phyto-free) were analyzed to determine the impact of dietary phytoestrogens on prostate weight and androgen receptor (AR) expression in the prostate. Results Dietary phytoestrogens significantly decreased post-pubertal prostate weight gain in Phyto-600 vs Phyto-free fed males. Additionally, dietary phytoestrogens (Phyto-600) decreased AR expression in the prostate as determined by in situ hybridization. Conclusions Soy phytoestrogens, present in diet, alter prostate growth presumably by binding ER-beta and subsequently reducing AR expression within the prostate.

Abstract Background In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit higher performance levels compared to females (a difference attributed to sex steroid hormonal influences). Based upon the results from our companion investigation, this study examined the influence of prenatal sex steroid hormone manipulations on VSM in adulthood, as assessed in the radial arm maze. Additionally, the influence of dietary soy phytoestrogens (i.e., the presence of high or low estrogen-like compounds present in the animal's diet) on VSM was examined in combination with the prenatal hormonal manipulations. Results Radial arm maze performance on a phytoestrogen-rich diet: 1) females treated prenatally with testosterone were masculinized and acquired/performed in a manner similar to control or oil-treated males and 2) males treated prenatally with an androgen receptor blocker (flutamide) were feminized and acquired/performed in a fashion typical of control or flutamide-treated females. When a diet change was initiated in adulthood, control phytoestrogen-rich fed females outperformed control females switched to a phytoestrogen-free diet. Whereas, in control males the opposite diet effect was identified. Furthermore, flutamide-treated males fed a phytoestrogen-rich diet outperformed flutamide-treated males switched to a phytoestrogen-free diet. Conclusions These results suggest that prenatal hormonal manipulations significantly sex-reverse the normal sexually dimorphic expression of VSM. Specifically, VSM was enhanced in females treated with testosterone and inhibited in males treated with flutamide. Finally, dietary soy phytoestrogens set a bias on learning and memory in these hormonally manipulated animals in a predictable manner and these data confirm and extend the findings in our companion paper (see Lund etal, BMC Neuroscience 2001 2:20).

Abstract Background In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit superior performance to females (a difference attributed to the hormonal influence of estrogen). This study examined the influence of phytoestrogens (estrogen-like plant compounds) on VSM, utilizing radial arm-maze methods to examine varying aspects of memory. Additionally, brain phytoestrogen, calbindin (CALB), and cyclooxygenase-2 (COX-2) levels were determined. Results Female rats receiving lifelong exposure to a high-phytoestrogen containing diet (Phyto-600) acquired the maze faster than females fed a phytoestrogen-free diet (Phyto-free); in males the opposite diet effect was identified. In a separate experiment, at 80 days-of-age, animals fed the Phyto-600 diet lifelong either remained on the Phyto-600 or were changed to the Phyto-free diet until 120 days-of-age. Following the diet change Phyto-600 females outperformed females switched to the Phyto-free diet, while in males the opposite diet effect was identified. Furthermore, males fed the Phyto-600 diet had significantly higher phytoestrogen concentrations in a number of brain regions (frontal cortex, amygdala & cerebellum); in frontal cortex, expression of CALB (a neuroprotective calcium-binding protein) decreased while COX-2 (an inducible inflammatory factor prevalent in Alzheimer's disease) increased. Conclusions Results suggest that dietary phytoestrogens significantly sex-reversed the normal sexually dimorphic expression of VSM. Specifically, in tasks requiring the use of reference, but not working, memory, VSM was enhanced in females fed the Phyto-600 diet, whereas, in males VSM was inhibited by the same diet. These findings suggest that dietary soy derived phytoestrogens can influence learning and memory and alter the expression of proteins involved in neural protection and inflammation in rats.

This narrative literature review examined the intricate relationship between body dysmorphic disorder (BDD) and dermatological conditions, with a brief focus on those characterized by conspicuous skin irregularities such as acne vulgaris, psoriasis, and vitiligo. Highlighting the significant prevalence of BDD among individuals afflicted with dermatological issues, our analysis illuminated the profound psychological repercussions stemming from an exaggerated preoccupation with perceived skin imperfections. Through an exploration of the underlying BDD symptoms, we analyzed the complex dynamics between skin health and mental well-being, emphasizing the disorder's impact on patients' psychological and social functioning. This narrative review further investigated the consequential effects of BDD on essential aspects of dermatological treatment, including patient adherence to therapeutic regimens, overall quality of life (QOL), and the effectiveness of available treatments. In addition to presenting current therapeutic approaches, we advocate for the integration of psycho-dermatological interventions tailored to mitigate the dual burden of skin conditions and psychological distress. Future research directions proposed include longitudinal studies to assess the long-term effects of BDD on skin disease prognosis and psychosocial well-being, which aim to refine and optimize treatment modalities to contribute to a more holistic understanding of BDD within dermatological practice., (© 2024. The Author(s).)

Background: While cannabidiol (CBD) and 4',7-isoflavandiol (Equol) have been examined individually in various skin studies, the present investigation tested whether topically applied CBD with Equol may yield enhanced effects on human skin biomarkers., Methods: After 24 hours exposure human skin gene expression was measured by quantitative polymerase chain reaction-messenger ribonucleic acid (qPCR-mRNA) analysis across 9 functional skin categories covering 97 biomarkers., Results: In general, among the biomarkers analyzed the CBD with Equol treatment displayed greater efficacy compared to CBD only or the Equol treatment alone (e.g., 4 out 5 for anti-acne, 15 out of 17 for anti-aging [e.g., collagen, elastin, calcium binding protein A7, tissue inhibitor of matrix metalloproteinase 1 ( TIMP 1 ), etc.], 19 out of 21 for anti-inflammatory (pain), 10 out of 11 for antioxidants to protect against oxidative stress, 6 out of 6 for circadian rhythm regulation for cell repair/restoration, 10 out of 15 for anti-pigmentation properties, 4 out of 5 for skin hydration, 6 out of 6 for tissue integrity, and 11 out of 12 for wound healing properties)., Conclusions: CBD with Equol displayed synergistic effects that may be an effective topical treatment for dermatology and cosmetic applications to improve human skin health and reduce photo-aging., Competing Interests: Edwin D. Lephart has no funding or sponsor conflicts of interest in the decision of the data/research presented in this report and regarding the publication of this manuscript. Edwin D. Lephart is an inventor on polyphenolic patents (US and worldwide) on various human health applications. Given the role as Guest Editor, Edwin D. Lephart had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Graham Pawelec., (© 2023 The Author(s). Published by IMR Press.)

Benign prostatic hyperplasia (BPH) is an age-related disorder, which is one of the most prevalent and costly benign neoplasms in men with over 94 million cases worldwide. Starting before or around 50 years of age, there is a linear increase in prostate volume and BPH symptoms, which are influenced by changes in hormonal, inflammatory, growth factors, cell receptor signaling, diet, physical activity, and the microbiome of the prostate that leads to cellular proliferation. While current pharmaceutical or surgical treatments are currently available, each treatment has serious side effects. This dilemma has motived men to seek treatment without negative side effects from medicinal plants such as botanicals, phytochemicals, and vitamins that have established safety records. This narrative overview focuses on several botanicals, phytochemicals and vitamins that are widely used in the treatment of BPH and emphasizes how, in some cases, combinations of these natural ingredients may provide better BPH symptom relief compared to utilization of a single medicinal plant product (monotherapy). Finally, this overview highlights in vitro, in vivo animal studies and mainly clinical data of journal reports published in the past 5 years from January 2018 to January 2023 on BPH and nutraceuticals. Notably, there is an evolving perspective or rethinking of the role that medicinal phytochemicals and natural vitamins usage play; that is, they may hold promise or are likely to alleviate BPH symptoms.

Emerging scientific advances in microbial research linking estrogens and the gut-skin microbiome in reference to dermal health are featured in this narrative review of journal reports and reviews from January 2018 through February 2022. Background information on advances in microbial research along with defining the microbiota and microbiome is presented in brief. The development of and factors that influence the gut microbiome in health and disease as well as the intrinsic and extrinsic factors influencing the skin microbiome and skin aging are summarized. New information on the development and changes of organ microbiomes have exposed similarities between skin and gut structure/function, microbial components/diversity/taxonomy and how they impact the immune response for combating disease and enhancing wellness. Estrogens promote health and support homeostasis in general and directly impact dermal health. Moreover, the gut, based upon the level of the microbial enzyme β-glucuronidase, which regulates estrogen's enterohepatic recirculation, constitutes a gut-skin microbial axis. This axis revolves around the systemically available estrogen to support immune function, counteract inflammation and oxidative stress, and decrease the risk of hormone-dependent skin cancers. These data support the direct effect of estrogens on skin health and the interaction of diet on dermal health via effects on the gut microflora. Finally, the potential for bioactive botanicals containing phytoestrogens or selective estrogen receptor modulators (SERMs) to evade the effects of gut β-glucuronidase expressing flora is proposed that may have a positive impact on skin., (© 2022. The Author(s).)

The overarching theme for this review is perspective. Superfoods (a marketing term for fruits and vegetables, etc.) have a positive connotation, while many superfoods contain phytoestrogens, a term that is alarming to the public and has a negative connotation because phytoestrogens are endocrine-disruptors, even though they are strong antioxidants that have many health benefits. To understand phytoestrogens, this paper provides a brief summary of the characteristics of: (a) estrogens, (b) estrogen receptors (ER), (c) estrogen-deficient skin, (d) how perspective(s) get off track, (e) phytoestrogen food sources, and (f) misconceptions of phytoestrogens and food safety, in general, that influence person(s) away from what is true. Finally, a brief history of cosmetics to nutraceuticals is covered plus the characteristics of phytoestrogens, resveratrol and equol on: (g) estrogen receptor binding, (h) topical and oral dosing, and (i) in vitro, molecular mechanisms and select clinical evidence, where both phytoestrogens (resveratrol and equol) demonstrate promising applications to improve skin health is presented along with future directions of nutraceuticals. Perspective is paramount in understanding the controversies associated with superfoods, phytoestrogens, and endocrine-disruptors because they have both positive and negative connotations. Everyone is exposed to and consumes these molecules everyday regardless of age, gender, or geographic location around the world, and how we understand this is a matter of perspective.

Estrogen is a pivotal signaling molecule; its production is regulated by the expression of the aromatase (CYP19A1) gene from ovarian and peripheral tissue sites, and it is transmitted via estrogen receptors to influence many important biological functions. However, the narrative for this overview focuses on the decline of 17β-estradiol levels from ovarian sites after menopause. This estrogen-deficient condition is associated with a dramatic reduction in skin health and wellness by negatively impacting dermal cellular and homeostatic mechanisms, as well as other important biological functions. The changes include loss of collagen, elastin, fibroblast function, vascularity, and increased matrix metalloproteinase(s) enzymatic activities, resulting in cellular and extracellular degradation that leads to dryness, wrinkles, atrophy, impaired wound healing/barrier function, decreased antioxidant capacity [i.e., defense against reactive oxygen species (ROS) and oxidative stress], decreased attractiveness and psychological health, and increased perception of aging. While topical estrogen may reverse these changes, the effects of today's low-dose systemic hormone treatments are not well established, raising the need for more concentrated local administration of hormones or newer cosmeceutical agents such as selective estrogen receptor modulators (SERMs), including phytoestrogens that have become major active ingredients for skin care products, especially when addressing estrogen-deficient skin. Two example compounds are presented, an analog of resveratrol (i.e., 4'-acetoxy resveratrol) and the isoflavonoid equol, both of which are involved in a variety of biochemical/molecular actions and mechanisms, as demonstrated via in vitro and clinical studies that enhance human dermal health, especially in estrogen-deficient skin.

Several journal reports, reviews, and commentaries over the last 20-25 years have pointed out the controversy attached to 17β-estradiol's inhibitory or stimulatory influence on hair follicle growth/cycling citing rodent (murine) and human results. While 17β-estradiol is the most potent sex steroid hormone in the body and has almost equal affinity for estrogen receptor (ER) alpha (α) and beta (β), there appears to be specific ER-mediated effects on scalp hair follicles/growth, etc. Additionally, the newly discovered G protein-coupled estrogen receptor (GPR30 or GPER) and the orphan receptor, estrogen-related receptor (ERR) gamma (γ), in skin and other tissue sites have potential impacts of how estrogens via these receptors may alter scalp hair characteristics, but this remains to be elucidated. Conversely, the negative impact of the 5α-reductase enzyme and its steroid product, 5α-dihydrotestosterone, on scalp hair growth is clear. Less clear is how 17β-estradiol is stimulatory in some scalp hair studies, but inhibitory in others. This brief summary examines the potential influences of steroidogenesis via aromatase (estrogen biosynthesis) and 5α-reductase expression, their enzyme activities, and steroid products along with the concepts of how steroid acute regulatory protein (StAR) and estrone sulfate may be involved in the complex hormonal, cellular/molecular signaling cascade of the hair follicle in growth and cycling., (© 2019 Wiley Periodicals, Inc.)

The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment to combat dermal aging is relatively new. For example, the term cosmeceutical was first coined by Albert Kligman in 1984 to describe topical products that afford both cosmetic and therapeutic benefits. However, beauty comes from the inside. Therefore, for some time scientists have considered how nutrition reflects healthy skin and the aging process. The more recent link between nutrition and skin aging began in earnest around the year 2000 with the demonstrated increase in peer-reviewed scientific journal reports on this topic that included biochemical and molecular mechanisms of action. Thus, the application of: (a) topical administration from outside into the skin and (b) inside by oral consumption of nutritionals to the outer skin layers is now common place and many journal reports exhibit significant improvement for both on a variety of dermal parameters. Therefore, this review covers, where applicable, the history, chemical structure, and sources such as biological and biomedical properties in the skin along with animal and clinical data on the oral applications of: (a) collagen, (b) ceramide, (c) β-carotene, (d) astaxanthin, (e) coenzyme Q 10 , (f) colostrum, (g) zinc, and (h) selenium in their mode of action or function in improving dermal health by various quantified endpoints. Lastly, the importance of the human skin microbiome is briefly discussed in reference to the genomics, measurement, and factors influencing its expression and how it may alter the immune system, various dermal disorders, and potentially be involved in chemoprevention.

Estrogens are known to have protective and favorable influences on skin health; conversely, androgens oppose the actions of estrogens. Estrogen's chemical messages are transmitted via the classical nuclear hormone estrogen receptors (ER) alpha and beta and the rapid-acting G-coupled membrane estrogen receptor. Androgens [both testosterone and 5α-dihydrotestosterone (5α-DHT)] bind the same androgen receptor. Estrogen levels peak in the mid- to late 20s in women and then decline by 50% by 50 years of age and dramatically decrease further after menopause. The loss of estrogens with aging contributes to diminished dermal health, whereas estrogen hormone therapy [eg, oral conjugated equine estrogens (CEE)] restores skin health. Several reports suggest positive correlations between the levels of circulating estrogens and: (1) perceived age, (2) attractiveness, (3) enhanced skin health, and (4) facial coloration in women. Based upon a psychological dermato-endocrine perspective, the positive correspondence of high estrogens levels with perceived age and facial attractiveness in women especially with aging demonstrates the importance of hormonal influences on observed dermal health and youthful appearance., (© 2018 Wiley Periodicals, Inc.)

Many cosmetic companies utilize in vitro gene array studies to display significant stimulation or inhibition of various human skin biomarkers to validate in vivo actions that are reported to enhance dermal health. This follows the central dogma of DNA-to-RNA results in protein expression; however, gene and protein expressions do not usually correlate. Unless both gene and protein expressions are quantified which require further investigational time and investment. Where data are available, this short commentary displays the in vitro comparison of four human skin biomarkers for the gene and protein expressions of the stimulation of collagen type I and elastin and the inhibition of matrix metalloproteinases 1 and 3, when equol was tested. The results demonstrate a good correspondence between gene and protein expressions for the human skin biomarkers tested., (© 2017 Wiley Periodicals, Inc.)

Resveratrol (RV) is a polyphenolic compound naturally produced by plants. Polyphenolic compounds incorporated into medicinal products are beneficial but, RV is rapidly metabolized with an associated decline in biological activity. This study tested RV as the standard and compared five structurally modified RV analogs: butyrate, isobutyrate, palmitoate, acetate, and diacetate (to improve functionality) at 1% concentration(s) for 24 h in epiderm full thickness cultures by gene array/qPCR mRNA analysis. When silent mating type information regulation 2 homolog 1, extracellular elements (collagen1A1, 3A1, 4A1; elastin, tissue inhibitor of matrix metalloproteinase 1, fibrillin 1 laminin beta1 and matrix metalloproteinase 9), anti-aging and aging genes, inflammatory biomarkers (interleukin-1A [IL1A], IL1R2, IL-6 and IL-8), nerve growth factor, and the antioxidants (proliferating cell nuclear antigen, catalase, superoxide dismutase and metallothionein 1H/2H) were evaluated, ranking each from highest-to-lowest for gene expression: butyrate > isobutyrate > diacetate > acetate > palmitoate. This study showed that the butyrate and isobutyrate analogs are more biologically active compared to resveratrol and have potential use in topical applications to improve dermal and other health applications. Impact statement Resveratrol has been reported to have a wide variety of health benefits but its rapid metabolism especially after oral ingestion results in very low bioavailability. Notably, the first human skin gene expression study of resveratrol was not published until 2014. The purpose of this study was to determine if increased stability and biological activity could be obtained by modifying the chemical structure of natural (trans) resveratrol and quantifying human gene expression by qPCR of skin biomarkers that enhance dermal health. Five resveratrol analogs were synthesized that increased their lipophilic index to enhance tissue penetration and augment biological activities on the measured parameters that expand the current knowledge of structure/function relationships. The butyrate and isobutyrate modifications displayed gene expression values significantly above resveratrol and suggest that oral application of these and potentially other resveratrol analogs may yield similar results to improve stability and biological activity to benefit/address various disorders/diseases.

Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best-known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17β-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4' acetoxy resveratrol (4AR), R -equol, racemic equol or S -equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R -equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5α-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S -equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6-fold. R -equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4' analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R -equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin.

Oxygen in biology is essential for life. It comes at a cost during normal cellular function, where reactive oxygen species (ROS) are generated by oxidative metabolism. Human skin exposed to solar ultra-violet radiation (UVR) dramatically increases ROS production/oxidative stress. It is important to understand the characteristics of human skin and how chronological (intrinsic) aging and photo-aging (extrinsic aging) occur via the impact of ROS production by cascade signaling pathways. The goal is to oppose or neutralize ROS insults to maintain good dermal health. Botanicals, as active ingredients, represent one of the largest categories used in dermatology and cosmeceuticals to combat skin aging. An emerging botanical is equol, a polyphenolic/isoflavonoid molecule found in plants and food products and via gastrointestinal metabolism from precursor compounds. Introductory sections cover oxygen, free radicals (ROS), oxidative stress, antioxidants, human skin aging, cellular/molecular ROS events in skin, steroid enzymes/receptors/hormonal actions and genetic factors in aging skin. The main focus of this review covers the characteristics of equol (phytoestrogenic, antioxidant and enhancement of extracellular matrix properties) to reduce skin aging along with its anti-aging skin influences via reducing oxidative stress cascade events by a variety of biochemical/molecular actions and mechanisms to enhance human dermal health., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Resveratrol (RV) 1, a plant polyphenol, has proven effective in commercial products yet drawbacks include low bioavailability due to rapid metabolism. Structural modifications have led to a 4'-acetoxy analog 2 (4AR) now produced using a selective one-step esterification reaction. The one-step synthesis is shown together with expression of skin genes using human dermal models to establish 4AR 2 benefits to skin health. 4AR 2 at 1% in qPCR experiments using a human skin model significantly increased gene expression of the anti-aging factor, SIRT 1 by over 3.3-fold, extracellular matrix proteins collagen III, IV, elastin and tissue inhibitors of metalloproteinases (TIMP 1, 2), anti-oxidants CAT, LOX, superoxide dismutase (SOD 1, 2), metallothioneins (MT1H, MT1H), skin aging biomarkers fibrillin (FBN1), laminin (LAMB1), proliferating cell nuclear antigen (PCNA), skin growth factors (HBEGF, IGF1, NGF and TGF). 4AR 2 also decreased gene expression of inflammatory and skin-aging molecules (IL-1, IL-6, IL-8, COX-2, TNGRSF) and S100 calcium binding proteins A8, A9. These findings suggest that 4AR 2 has potential for topically treatment and prevention of skin aging., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Diets high in soy and selenium (Se) decrease prostate cancer risk factors in healthy rats. The purpose of this study was to determine whether treatment with high levels of soy and/or supplemental Se would decrease prostate cancer risk factors in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse, and whether timing of the introduction of these nutrients would affect risk reduction., Methods: Male hemizygous [C57BL/6 × FVB]F1 TRAMP mice were exposed to stock diets high or devoid of soy, with or without a supplement of Se-methylselenocysteine (MSC) starting at conception (10 mg Se/L in drinking water of pregnant/nursing dams; daily bolus of 4 mg Se/kg body weight to pups after weaning) or at 6 weeks of age in a 2 × 2 factorial design. Mice were killed at 12 weeks (n per dietary treatment = 20-30)., Results: Liver and serum Se concentrations were increased by MSC supplementation (P < 0.001), high-soy diet (P < 0.05), and initiation of dietary treatments at conception (P < 0.05). MSC supplementation had greater effects in mice fed the zero-soy basal diet, compared to the high-soy formulation (Pinteraction  < 0.01). These same three interventions, individually and interactively, decreased body weight and epididymal fat pad weights, and steady state levels of mRNA for Cyp19a1 (aromatase) and Srd5a1 (5α-reductase). In contrast, MSC was the only treatment that decreased urogenital tract weights (P < 0.001), serum IGF-1 levels (P < 0.002), and Gleason scores (P < 0.05)., Conclusions: Supplemental MSC reduces risk of prostate cancer in TRAMP mice. Basal diet composition (zero- vs. high-soy) can modify MSC's chemopreventive effects. Initiation of dietary treatments from conception maximizes chemopreventive effects of MSC. Prenatal Se status may have long-lasting effects on development and progression of prostate cancer., (© 2016 Wiley Periodicals, Inc.)

The aromatase enzyme catalyzes the conversion of androgens to estrogens in many human tissues. Estrogens are known to stimulate cellular proliferation associated with certain cancers and protect against adverse symptoms during the peri- and postmenopausal intervals. Phytoestrogens are a group of plant derived naturally occurring compounds that have chemical structures similar to estrogen. Since phytoestrogens are known to be constituents of animal/human food sources, these compounds have received increased research attention. Phytoestrogens may contribute to decreased cancer risk by the inhibition of aromatase enzyme activity and CYP19 gene expression in human tissues. This review covers (a) the aromatase enzyme (historical descriptions on function, activity, and gene characteristics), (b) phytoestrogens in their classifications and applications to human health, and (c) a chronological coverage of aromatase activity modulated by phytoestrogens from the early 1980s to 2015. In general, phytoestrogens act as aromatase inhibitors by (a) decreasing aromatase gene expression, (b) inhibiting the aromatase enzyme itself, or (c) in some cases acting at both levels of regulation. The findings presented herein are consistent with estrogen's impact on health and phytoestrogen's potential as anticancer treatments, but well-controlled, large-scale studies are warranted to determine the effectiveness of phytoestrogens on breast cancer and age-related diseases.

Context: Equol is a polyphenolic/isoflavonoid molecule that can be expressed as isomers. However, the characteristics of the equol isomers on dermal gene/protein expression and human skin percutaneous absorption remain unknown., Objective: Perform a comprehensive investigation on equol as: R-equol, racemic equol or S-equol to determine their differential expression of skin-related genes, quantify collagen expression and determine percutaneous absorption in human skin., Methods: Quantified: (i) gene expression/mRNA levels via gene array technology using human skin equivalents with equol exposure at 1.2% in qPCR experiments, (ii) in vitro collagen expression in human fibroblasts, and (iii) percutaneous absorption by Franz cell techniques., Results: In the qPCR studies, only three genes displayed the greatest significant expression by S-equol, whereas 16 genes displayed the greatest significant levels (either stimulation or inhibition) by R-equol and/or racemic equol, such as extracellular matrix proteins (i.e., collagen and elastin), nerve growth factor, aging genes [FOS, 100 A8 and A9 calcium-binding proteins, 5α-reductase type 1, and matrix metalloproteinases (1, 3, and 9)], and inflammatory genes (e.g., interleukin-1 alpha, interleukin-6, and cyclooxygenase-1). Collagen type I expression in fibroblasts was greater with racemic versus S-equol treatment at 1 and 10 nM. Percutaneous absorption demonstrated high sequestering in keratinocytes with subsequent accumulation/release over time., Discussion and Conclusion: Overall, these results illustrate the significant differences in mirror-image molecules or isomers of equol where R-equol and/or racemic equol are better molecules for skin gene expression compared to S-equol and the percutaneous absorption of equol represents a unique epidermal reservoir delivery mechanism.

Background: High dietary intake of soy or selenium (Se) is associated with decreased risk of prostate cancer. Soy constituents and various chemical forms of Se have each been shown to downregulate expression of the androgen receptor (AR) and AR-regulated genes in the prostate. We hypothesized that downregulation of AR and AR-regulated genes by the combination of these dietary components would inhibit tumorigenesis in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse., Methods: Male mice were exposed from conception to stock diets high or low in soy, with or without a supplement of Se-methylseleno-L-cysteine (MSC) in a 2 × 2 factorial design. Mice were sacrificed at 18 weeks. Prostate histopathology, urogenital tract (UGT) weight, hepatic activity of androgen-metabolizing enzymes, and expression of AR, AR-regulated, and AR-associated FOX family genes, in the dorsolateral prostate were examined., Results: High soy intake decreased activity of hepatic aromatase and 5α-reductase, expression of AR, AR-regulated genes, FOXA1, UGT weight, and tumor progression, and upregulated protective FOXO3. Supplemental MSC upregulated AKR1C14, which reduces 5α-dihydrotestosterone., Conclusions: Soy is an effective pleiotropic dietary agent for prevention of prostate cancer. The finding of effects of soy on FOX family gene expression in animals is novel. Combination effects of supplemental MSC may depend upon the soy content of the basal diet to which it is added., (Copyright © 2013 Wiley Periodicals, Inc.)

The 4'-ester analog of the disease preventative resveratrol 1 (RV), 4'-acetyl-RV 2 along with 4'-pivaloate 13 and benzoate 14 RV were synthesized. The previously developed palladium catalyzed decarbonylative Heck coupling was used to assemble the stilbene core together with 3,5-dibenzyl protected phenol intermediates that allowed for efficient coupling and deprotection using boron trifluoride etherate. Studies with Long-Evans rats were performed to establish safety, toxicity, and behavioral parameters. In addition, the Porsalt forced-swim test was used to demonstrate anti-depressant activity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the effects of equol, a plant and intestinal flora derived isoflavonoid molecule on the expression of skin genes and proteins using human dermal models. As equol has been shown to mimic 17β-estradiol and bind specifically to 5α-dihydrotestostone (5α-DHT), these agents were used (in addition to equol) to determine whether equol may play important and beneficial roles in the extracellular matrix (ECM). Equol at 0.3 or 1.2% in qPCR experiments using a human skin barrier model examined ECM gene expression. Equol, 5α-DHT, and 17β-estradiol at 10 nM were studied in human monolayer fibroblasts cultures (hMFC) for ECM protein expression. Human fibroblast three-dimensional organotypic cultures revealed equol's influence (@ 10 nM) on ECM proteins via fluorescent-activated cell sorting (FACS) analysis. In qPCR experiments, equol significantly increased collagen, elastin (ELN), and tissue inhibitor of metalloprotease and decreased metalloproteinases (MMPs) gene expression and caused significant positive changes in skin antioxidant and antiaging genes. In hMFC, equol significantly increased collagen type I (COL1A1), whereas, 5α-DHT significantly decreased cell viability that was blocked by equol. FACS analysis showed equol and 17β-estradiol significantly stimulated COL1A1, collagen type III (COL3A1), and ELN while MMPs were significantly decreased compared with control values. Finally, tamoxifen blocked the positive influences of equol on ECM proteins via FACS analysis. These findings suggest that equol has the potential to be used topically for the treatment and prevention of skin aging, by enhancing ECM components in human skin., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

The effects of supplemental Se in rodent models may depend upon composition of the basal diet to which it is added. Wild-type male littermates of Transgenic Adenocarcinoma of Mouse Prostate mice were fed until 18 wk of age 1 of 2 Se-adequate stock diets high in soy (HS) or low in phytoestrogens (LP) or the same diets supplemented with 3.0 mg Se/kg diet as seleno-methylselenocysteine. Body and abdominal fat pad weights were lower (P < 0.01) in mice fed the HS diet. Supplemental Se reduced fat pad weights in mice receiving the LP diet but increased body and fat pad weights in mice consuming the HS formulation (P-interaction < 0.005). Serum free triiodothyronine concentrations were unaffected by supplemental Se in mice fed the LP diet but were decreased by Se supplementation of mice given the HS feed (P-interaction < 0.02). Free thyroxine concentrations were higher in mice consuming the HS diet regardless of Se intake (P < 0.001). Hepatic mRNA for iodothyronine deiodinase I was lower (P < 0.001) in mice fed the HS diet. Supplementation of Se increased this mRNA (P < 0.001) in both diet groups. Results from this study show a significant interaction between the composition of basal diets and the effects of supplemental Se with respect to body composition. These findings have important implications for future studies in rodent models of the effects of supplemental Se on heart disease, cancer, diabetes, and other conditions related to body weight and composition.

Background: Soy-derived isoflavones potentially protect against obesity and depression. In five different studies we examined the influence of soy-containing diets or equol injections on depression, serotonin levels, body weight gain (BW) and white adipose tissue (WAT) deposition in female Long-Evans rats at various stages of life [rats were intact, ovariectomized or experienced natural ovarian failure (NOF)]., Results: In general, animals fed a soy-rich diet (Phyto-600) and/or administered equol (@ 5 mg/kg/day) displayed significant decreases in BW and WAT compared to a low-soy diet. When equol was injected alone (5 mg/kg/day), experiments 1, 4, and 5 demonstrated that body weight was significantly decreased. Equol has body weight control effects in females that are dependent on ovarian status and/or age of diet initiation. Experiments 1-4 all displayed no significant differences in depressive-related behavior as measured by the Prosolt forced swim test (PFST) when soy-rich (Phyto-600) or low-soy diets (Phyto-low) or equol treatments (5 mg/kg/day) were tested in female rats at various ages or hormonal status. Results of all the experiments are not presented here due to space limitations, but data from experiment 5 are presented. From conception female rats were exposed to either: a) a soy-rich (Phyto-600) or b) low-soy diet (Phyto-low). After 290 days all rats experienced NOF. At 330 days-old the animals were examined in the Porsolt forced swim test (PFST). One month later a second PFST was performed [after Phyto-low fed animals were injected with equol (5 mg/kg/day) for one week prior to the second PFST]. At the first PFST, serotonin and mobility levels were significantly decreased in the Phyto-low fed animals compared to animals that consumed the Phyto-600 diet. After equol injections at the second PFST, mobility and serotonin levels significantly increased in aged NOF rats fed the Phyto-low diet (to levels comparable to Phyto-600 fed animals)., Conclusions: Consumption of dietary isoflavones or equol exposure in rats has body weight controlling effects and equol specifically may have antidepressant potential dependent upon diet initiation and/or dosage of treatments. The current study demonstrates that equol is able to decrease body weight, abdominal WAT, and depressive-related behavior. While other factors and mechanisms may play a role, in part, the present results provide a greater understanding of how isoflavonoid molecules modulate the brain's influence on behavior.

Background: To determine: in vitro binding affinity of equol for 5alpha-dihydrotestosterone (5alpha-DHT), in vitro effects of equol treatment in human prostate cancer (LNCap) cells, and in vivo effects of equol on rat prostate weight and circulating levels of sex steroid hormones., Methods: First, in vitro equol binding affinity for 5alpha-DHT was determined using 14C5alpha-DHT combined with cold 5alpha-DHT (3.0 nM in all samples). These steroids were incubated with increasing concentrations of equol (0-2,000 nM) and analyzed by Sephadex LH-20 column chromatography. 14C5alpha-DHT peak/profiles were determined by scintillation counting of column fractions. Using the 14C5alpha-DHT peak (0 nM equol) as a reference standard, a binding curve was generated by quantifying shifts in the 14C5alpha-DHT peaks as equol concentrations increased. Second, equol's in vitro effects on LNCap cells were determined by culturing cells (48 hours) in the presence of increasing concentrations of dimethyl sulfoxide (DMSO) (vehicle-control), 5alpha-DHT, equol or 5alpha-DHT+equol. Following culture, prostate specific antigen (PSA) levels were quantified via ELISA. Finally, the in vivo effects of equol were tested in sixteen male Long-Evans rats fed a low isoflavone diet. From 190-215 days, animals received 0.1 cc s.c. injections of either DMSO-control vehicle (n = 8) or 1.0 mg/kg (body weight) of equol (in DMSO) (n = 8). At 215 days, body and prostate weights were recorded, trunk blood was collected and serum assayed for luteinizing hormone (LH), 5alpha-DHT, testosterone and 17beta-estradiol levels., Results: Maximum and half maximal equol binding to 5alpha-DHT occurred at approximately 100 nM and 4.8 nM respectively. LNCap cells cultured in the presence of 5alpha-DHT significantly increased PSA levels. However, in the presence of 5alpha-DHT+equol, equol blocked the significant increases in PSA levels from LNCap cells. In vivo equol treatment significantly decreased rat prostate weights and serum 5alpha-DHT levels but did not alter LH, testosterone, and estradiol levels., Conclusions: Equol administration appears to have potential beneficial effects for prostate health and other 5alpha-DHT mediated disorders. Equol administration: reduces PSA levels from LNCap cells under 5alpha-DHT stimulation, decreases rat prostate size, decreases serum 5alpha-DHT levels and androgen hormone action, while not altering other circulating sex steroids or LH levels.

Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague-Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n=8-9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3+/-4.19; D, 18.4+/-1.54; P<0.05), but increased renal (ND, 1.83+/-0.92; D, 7.85+/-1.38; P<0.05) and ocular (D, 23.4+/-3.66; D, 87.1+/-28.1; P<0.05) aromatase activity. This increase in renal (Dcas, 6.30+/-1.25) and ocular (Dcas, 62.7+/-11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31+/-0.01; D, 0.51+/-0.11; Dcas, 0.45+/-0.08) as well as estrogen receptor alpha protein expression (ND, 0.63+/-0.09; D, 1.62+/-0.28; Dcas, 1.38+/-0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17alpha-diol (3alpha-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3alpha-diol levels. Chronic, long-term (1-4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3alpha-diol, respectively, could reverse age-associated decline in performance. 3alpha-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3alpha-diol production and 3alpha-diol administration reinstates cognitive and affective performance of aged male rats.

Background: High dietary intake of selenium or soybean isoflavones reduces prostate cancer risk. These components each affect androgen-regulated gene expression. The objective of this work was to determine the combined effects of selenium and isoflavones on androgen-regulated gene expression in rat prostate., Methods: Male Noble rats were exposed from conception until 200 days of age to diets containing an adequate (0.33-0.45 mg/kg diet) or high (3.33-3.45 mg/kg) concentration of selenium as Se-methylselenocysteine and a low (10 mg/kg) or high (600 mg/kg) level of isoflavones in a 2 x 2 factorial design. Gene expression in the dorsolateral prostate was determined for the androgen receptor, for androgen-regulated genes, and for Akr1c9, whose product catalyzes the reduction of dihydrotestosterone to 5alpha-androstane-3alpha, 17beta-diol. Activity of hepatic glutathione peroxidise 1 and of prostatic 5alpha reductase were also assayed., Results: There were no differences due to diet in activity of liver glutathione peroxidase activity. Total activity of 5alpha reductase in prostate was significantly lower (p = 0.007) in rats fed high selenium/high isoflavones than in rats consuming adequate selenium/low isoflavones. High selenium intake reduced expression of the androgen receptor, Dhcr24 (24-dehydrocholesterol reductase), and Abcc4 (ATP-binding cassette sub-family C member 4). High isoflavone intake decreased expression of Facl3 (fatty acid CoA ligase 3), Gucy1a3 (guanylate cyclase alpha 3), and Akr1c9. For Abcc4 the combination of high selenium/high isoflavones had a greater inhibitory effect than either treatment alone. The effects of selenium on gene expression were always in the direction of chemoprevention, Conclusion: These results suggest that combined intake of high selenium and high isoflavones may achieve a greater chemopreventive effect than either compound supplemented individually.

Background: High dietary intake of selenium or isoflavones reduces risk factors for prostate cancer. We tested whether combined supplementation of these two dietary components would reduce prostate cancer risk factors in rats more than supplementation of each component individually., Methods: Male Noble rat pups were exposed from conception to diets containing an adequate (0.33-0.45 mg/kg diet) or high (3.33-3.45 mg/kg) concentration of selenium as Se-methylselenocysteine and a low (10 mg/kg) or high (600 mg/kg) level of isoflavones in a 2 x 2 factorial design. Pups consumed their respective diets until sacrifice at 35, 100, or 200 days. Male Noble rat breeders, whose exposure to the diets began after puberty, were sacrificed at 336 days. Rats were weighed biweekly. Blood was collected at the time of sacrifice and body fat and prostates were dissected and weighed. Serum levels of leptin, IGF-1, and testosterone were determined using ELISA kits. Serum levels of isoflavones were assayed by GC/MS. Liver activity of selenium-dependent glutathione peroxidase 1 was measured as an indicator of selenium status., Results: Serum isoflavone concentrations were nearly 100-fold higher at 35 days of age (1187.1 vs. 14.4 ng/mL, mean +/- SD) in pups fed the high vs. low isoflavone diets, and remained so at 100 and 200 days, and in breeders. There were no dietary differences in liver glutathione peroxidase activity in pups or breeders. High isoflavone intake significantly (p = 0.001-0.047) reduced body weight in rat pups from 35 days onward, but not in breeders. Body fat and leptin were likewise significantly reduced by high isoflavones in pups while effects in breeders were less pronounced but still significant. High intake of Se and isoflavones each decreased serum IGF-1 in pups at 100 and 200 days, but not in breeders. No consistent dietary effects were observed on serum testosterone or relative weights of prostates. In pups, the combination of high isoflavones and high selenium produced the lowest weight gain, the lowest serum leptin, and the lowest serum IGF-1 concentrations of all four diets., Conclusion: Combined intake of high selenium and high isoflavones may achieve greater chemopreventive effects than either compound individually. The timing of supplementation may determine the significance of its effects.

Background: Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. Few studies have examined the nociception and stress hormone responses after consumption of soy isoflavones., Methods: In this study, ovariectomized (OVX) female Long-Evans rats were fed either an isoflavone-rich diet (Phyto-600) or an isoflavone-free diet (Phyto-free). We examined the effects of soy isoflavones on metabolism by measuring body weights, food/water intake, adipose tissue weights as well as serum leptin levels. Also, circulating isoflavone levels were quantified. During chemically induced estrous, nociceptive thresholds were recorded. Then, the animals were subjected to a stressor and stress hormone levels were quantified., Results: Body weights were significantly lower in Phyto-600 fed rats compared to Phyto-free values within one week and during long-term consumption of soy isoflavones. Correspondingly, Phyto-600 fed animals displayed significantly less adipose deposition and lower serum leptin levels than Phyto-free values. However, rats on the Phyto-600 diet displayed greater food/water intake compared to Phyto-free levels. No changes in thermal pain threshold or stress hormone levels (ACTH and corticosterone) were observed after activation of the hypothalamic-pituitary-adrenal (HPA) stress axis., Conclusion: In summary, these data show that consumption of soy isoflavones 1) increases metabolism, demonstrated by significantly decreased body weights, adipose tissue deposition and leptin levels, but 2) does not alter nociception or stress hormone responses, as indexed by thermal pain threshold, serum corticosterone and ACTH levels in chemically-induced estrous OVX rats.

Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. There is evidence that soy isoflavones influence neuronal apoptosis or proliferation in vitro and in vivo. However, little research has been done to investigate the effects of soy isoflavones on markers of neuronal apoptosis and survival in vivo. We examined brain BAD (a proapoptotic member of Bcl-2 protein family) and neuron-specific beta III tubulin (an early marker of neuronal differentiation/survival) levels in male rats fed either a standard chow rich of soy isoflavones (Phyto-600) or one free of soy isoflavones (Phyto-free) life-long (from conception until time tissue collected). Among five brain regions, the expression of BAD was highest in medial basal hypothalamus (MBH); the next highest in hippocampus; moderate in amygdala and frontal cortex; and lowest in cerebellum in Phyto-free fed animals. In animals on Phyto-600 diet, the levels of BAD were significantly decreased in frontal cortex and MBH; but significantly increased in the amygdala. The expression of beta III tubulin was highest in frontal cortex; moderate in amygdala, hippocampus and MBH; and lowest in cerebellum in the Phyto-free group. In rats fed with the Phyto-600 diet, levels of beta III tubulin were significantly increased in amygdala, frontal cortex, hippocampus and MBH compared to Phyto-free values. In summary, these findings provide evidence for the neuroprotective potential of soy isoflavones in the amygdala, frontal cortex, hippocampus and MBH. This implies that consumption of soy isoflavones may be beneficial on learning and memory, anxiety-related behaviors, and recovery from trauma.

Background: The discovery of equol in human urine more than 2 decades ago and the finding that it is bacterially derived from daidzin, an isoflavone abundant in soy foods, led to the current nutritional interest in soy foods. Equol, unlike the soy isoflavones daidzein or genistein, has a chiral center and therefore can occur as 2 distinct diastereoisomers., Objective: Because it was unclear which enantiomer was present in humans, our objectives were to characterize the exact structure of equol, to examine whether the S- and R-equol enantiomers are bioavailable, and to ascertain whether the differences in their conformational structure translate to significant differences in affinity for estrogen receptors., Design: With the use of chiral-phase HPLC and mass spectrometry, equol was isolated from human urine and plasma, and its enantiomeric structure was defined. Human fecal flora were cultured in vitro and incubated with daidzein to ascertain the stereospecificity of the bacterial production of equol. The pharmacokinetics of S- and R- equol were determined in 3 healthy adults after single-bolus oral administration of both enantiomers, and the affinity of each equol enantiomer for estrogen receptors was measured., Results: Our studies definitively establish S-equol as the exclusive product of human intestinal bacterial synthesis from soy isoflavones and also show that both enantiomers are bioavailable. S-equol has a high affinity for estrogen receptor beta (K(i) = 0.73 nmol/L), whereas R-equol is relatively inactive., Conclusions: Humans have acquired an ability to exclusively synthesize S-equol from the precursor soy isoflavone daidzein, and it is significant that, unlike R-equol, this enantiomer has a relatively high affinity for estrogen receptor beta.

Because of their protective effects in age-related diseases and hormone-dependent cancers, the use of phytoestrogens (isoflavones) as 'natural' remedies has gained prominence. Isoflavones are estrogen mimics that bind estrogen receptors and act like natural selective estrogen receptors modulators. However, limited data exists regarding the influence of soy-derived dietary isoflavones in brain. This brief review will address these topics and examine the influence of dietary isoflavones on sexually dimorphic hypothalamic nuclei. We have observed that altering the isoflavone content within diet significantly affects both the sexually dimorphic nucleus of the preoptic area (a structure that is larger in males than in females) and the anteroventral periventricular nucleus (a structure that is larger in females than in males). Specifically, when animals were switched from phytoestrogen-rich to a phytoestrogen-free diet the volume of the sexually dimorphic nucleus of the preoptic area was decreased in males (no alterations were detected in females). Conversely, when the anteroventral periventricular nucleus was examined, volume changes were recorded in males and females opposite to the patterns observed for the sexually dimorphic nucleus of the preoptic area. Given the practical limitations of examining the effects of dietary phytoestrogens in the human brain, it is important to establish comparative data sets to elucidate phytoestrogen's hormone action and potentially its beneficial brain health effects.

Phytoestrogens have received increased investigative attention due to their potential protective effects in connection to age-related diseases and hormone-dependent cancers. Phytoestrogens appear to be an effective treatment during perimenopause where symptoms, such as hot flashes are reduced. However, little is known about the influence of phytoestrogens on core body temperature during various hormonal conditions. This study examined the effects of dietary phytoestrogens on core body temperature during estrous cycles or pregnancy by feeding Long-Evans rats either a diet rich in phytoestrogens (Phyto-600) versus a diet relatively low in phytoestrogens (Phyto-free). Independent of treatments, body temperature was highest at proestrus and declined during estrus and diestrus. Moreover, the consumption of the Phyto-600 diet moderately decreased body temperature during proestrus, estrus and diestrus versus Phyto-free-fed animals. During pregnancy, independent of treatments, core body temperature decreased as a function of increasing gestational length. Phyto-600-fed rats displayed significantly decreased body temperatures (by approximately 0.5 degrees C) from gestation days 6 to 19, compared to Phyto-free values. The results from this study indicate that consumption of dietary phytoestrogens alters the neuroendocrine mechanism of core body temperature regulation that may help explain, in part, the beneficial effects of phytoestrogens for hot flashes.

BACKGROUND: Phytoestrogens derived from soy foods (or isoflavones) have received prevalent usage due to their 'health benefits' of decreasing: a) age-related diseases, b) hormone-dependent cancers and c) postmenopausal symptoms. However, little is known about the influence of dietary phytoestrogens on regulatory behaviors, such as food and water intake, metabolic hormones and neuroendocrine parameters. This study examined important hormonal and metabolic health issues by testing the hypotheses that dietary soy-derived isoflavones influence: 1) body weight and adipose deposition, 2) food and water intake, 3) metabolic hormones (i.e., leptin, insulin, T3 and glucose levels), 4) brain neuropeptide Y (NPY) levels, 5) heat production [in brown adipose tissue (BAT) quantifying uncoupling protein (UCP-1) mRNA levels] and 6) core body temperature. METHODS: This was accomplished by conducting longitudinal studies where male Long-Evans rats were exposed (from conception to time of testing or tissue collection) to a diet rich in isoflavones (at 600 micrograms/gram of diet or 600 ppm) vs. a diet low in isoflavones (at approximately 10-15 micrograms/gram of diet or 10-15 ppm). Body, white adipose tissue and food intake were measured in grams and water intake in milliliters. The hormones (leptin, insulin, T3, glucose and NPY) were quantified by radioimmunoassays (RIA). BAT UCP-1 mRNA levels were quantified by PCR and polyacrylamide gel electrophoresis while core body temperatures were recorded by radio telemetry. The data were tested by analysis of variance (ANOVA) (or where appropriate by repeated measures). RESULTS: Body and adipose tissue weights were decreased in Phyto-600 vs. Phyto-free fed rats. Food and water intake was greater in Phyto-600 animals, that displayed higher hypothalamic (NPY) concentrations, but lower plasma leptin and insulin levels, vs. Phyto-free fed males. Higher thyroid levels (and a tendency for higher glucose levels) and increased uncoupling protein (UCP-1) mRNA levels in brown adipose tissue (BAT) were seen in Phyto-600 fed males. However, decreased core body temperature was recorded in these same animals compared to Phyto-free fed animals. CONCLUSIONS: This study demonstrates that consumption of a soy-based (isoflavone-rich) diet, significantly alters several parameters involved in maintaining body homeostatic balance, energy expenditure, feeding behavior, hormonal, metabolic and neuroendocrine function in male rats.

The early discontinuation of the Women's Health Initiative trial evaluating the effects of estrogen plus progestin due to concerns about the risk-benefit ratio of this steroid combination therapy emphasizes the need to examine alternative methods of estrogen replacement. One such alternative is isoflavone consumption of soy-derived dietary phytoestrogens that have received prevalent usage due to their ability to decrease age related disease (cardiovascular and osteoporosis), hormone-dependent cancers (breast and prostate), and peri- and postmenopausal symptoms. Differences in dietary phytoestrogen consumption result in large variations in somatic phytoestrogen content. These molecules affect estrogen and estrogen receptor function in several ways, including having both agonist and antagonist effects on estrogen receptors, as well as functioning like natural selective estrogen receptor modulators. Similar to estrogens, dietary phytoestrogens appear to affect certain aspects of vascular, neuroendocrine, and cognitive function. This article reviews health effects of estrogen, isoflavones and their hormonal mechanism of action, brain penetration by isoflavones, heath effects of isoflavones, and effects of isoflavones on vascular, neuroendocrine, and cognitive function. Because of their diverse health effects and widespread availability in soy foods, dietary phytoestrogens merit continued research into their effects on human health and cognitive function.

Equol (7-hydroxy-3[4'hydroxyphenyl]-chroman) is the major metabolite of the phytoestrogen daidzein, one of the main isoflavones found abundantly in soybeans and soy foods. Equol may be an important biologically active molecule based on recent studies demonstrating that equol can modulate reproductive function. In this study, we examined the effects of equol on prostate growth and LH secretion and determined some of the mechanisms by which it might act. Administration of equol to intact male rats for 4-7 days reduced ventral prostate and epididymal weight and increased circulating LH levels. Using binding assays, we determined that equol specifically binds 5alpha-dihydrotestosterone (DHT), but not testosterone, dehydroepiandrosterone, or estrogen with high affinity. Equol does not bind the prostatic androgen receptor, and has a modest affinity for recombinant estrogen receptor (ER) beta, and no affinity for ERalpha. In castrated male rats treated with DHT, concomitant treatment with equol blocked DHT's trophic effects on the ventral prostate gland growth and inhibitory feedback effects on plasma LH levels without changes in circulating DHT. Therefore, equol can bind circulating DHT and sequester it from the androgen receptor, thus altering growth and physiological hormone responses that are regulated by androgens. These data suggest a novel model to explain equol's biological properties. The significance of equol's ability to specifically bind and sequester DHT from the androgen receptor have important ramifications in health and disease and may indicate a broad and important usage for equol in the treatment of androgen-mediated pathologies.