Phytoestrogens as alternative hormone replacement therapy in menopause: What is real, what is unknown.

Journal of Steroid Biochemistry & Molecular Biology 143 (2014) 61–71

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Review

Phytoestrogens as alternative hormone replacement therapy in menopause: What is real, what is unknown Ana C. Moreira a,b,c , Ana M. Silva b,c , Maria S. Santos b,c , Vilma A. Sardão b,∗ a b c

Doctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal Department of Life Sciences, University of Coimbra, Coimbra, Portugal

a r t i c l e

i n f o

Article history: Received 4 October 2013 Received in revised form 3 January 2014 Accepted 29 January 2014 Available online 28 February 2014 Keywords: Menopause Hormone replacement therapy Phytoestrogens Toxicology

a b s t r a c t Menopause is characterized by an altered hormonal status and by a decrease in life quality due to the appearance of uncomfortable symptoms. Nowadays, with increasing life span, women spend one-third of their lifetime under menopause. Understanding menopause-associated pathophysiology and developing new strategies to improve the treatment of menopausal-associated symptoms is an important topic in the clinic. This review describes physiological and hormone alterations observed during menopause and therapeutic strategies used during this period. We critically address the benefits and doubts associated with estrogen/progesterone-based hormone replacement therapy (HRT) and discuss the use of phytoestrogens (PEs) as a possible alternative. These relevant plant-derived compounds have structural similarities to estradiol, interacting with cell proteins and organelles, presenting several advantages and disadvantages versus traditional HRT in the context of menopause. However, a better assessment of PEs safety/efficacy would warrant a possible widespread clinical use. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of estrogens in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Menopausal symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormone replacement therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Estradiol-based therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Phytoestrogens: structure, origin and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Estrogenic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Biologic effects during menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1. Menopausal classic symptoms and phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3. Cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.4. Neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.5. Other therapeutic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.6. Phytoestrogens cellular interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.7. Toxicity of phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62 62 62 64 64 64 65 65 65 65 66 66 66 66 66 67 67

Abbreviations: Akt, protein kinase B; AMPK, 5 AMP-activated protein kinase; BBB, blood-brain barrier; COX2, cyclooxygenase 2; E2, estradiol; EGTA, ethylene glycol tetraacetic acid; ER, estrogen receptor; ERE, Estrogen-responsive elements; ERK, Extracellular signal-regulated kinases; FSH, follicle-stimulating hormone; GPR, G proteincoupled receptor; HRT, Hormone replacement therapy; iNOS, inducible nitric oxide synthase; IL-1␤, interleukin 1 beta; JNK, c-Jun N-terminal kinases; LH, luteinizing hormone; MMP, matrix metalloproteinase; NAD+ , Nicotinamide adenine dinucleotide; PE (s), phytoestrogen (s); PTEN, Phosphatase and tensin homolog; RANK, Receptor Activator of Nuclear Factor ␬ B; ROS, Reactive oxygen species; SOD, Superoxide dismutase; TNF-␣, tumor necrosis factor alpha; TRAP, Tartrate-resistant acid phosphatase; WHI, Women’s Health Initiative. ∗ Corresponding author at: Center for Neuroscience and Cell Biology, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal. Tel.: +351 239 855 760; fax: +351 239 853 409. E-mail address: [email protected] (V.A. Sardão). 0960-0760/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsbmb.2014.01.016

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A.C. Moreira et al. / Journal of Steroid Biochemistry & Molecular Biology 143 (2014) 61–71

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The women’s reproductive stage is controlled by autocrine, paracrine and endocrine factors, which regulate female development, especially the maturation of the ovarian follicle, ovulation, luteinisation and endometrium remodeling. Healthy women are expected to spend in average 36 years in a reproductive life span. However, with increasing life expectancy, women spend one-third of their lifetime under menopause. The hormonal alterations that occur during menopause, such as the decrease in 17-␤-estradiol (E2) and the increase in follicle-stimulating hormone (FSH) trigger several alterations in the body, increasing the risk for the development of several pathologies. The transition to menopause is challenging for the majority of women, with an estradiol-based therapy (hormone replacement therapy, HRT) being in general used to minimize physiological alterations associated with menopause. However, several problems are associated with HRT, justifying the need for therapeutic alternatives. In this scenario, phytoestrogens (PEs) gain importance due to their chemical resemblance to E2 (Fig. 1). Here, we discuss the pros and cons associated with PEsbased therapy during menopause, a relevant topic in the clinic since the use of those compounds is increasing. 2. The role of estrogens in women Estrogens are steroid hormones, which generate and regulate the menstrual cycle. Estrogens are mainly produced in the theca interna cells of ovaries resulting from the conversion of cholesterol to androstenedione or testosterone, being subsequently aromatized to estrone and estradiol in granulosa cells [1]. Estrogens can also be produced in the corpus luteum and placenta [2] or in non-traditional sources including adrenal glands, adipose tissue, brain and breast [3]. Estrogens promote the development and maintenance of the female reproductive system and secondary sexual characteristics. The latter include breast development, typical female body proportions, distribution of subcutaneous adipose tissue and the characteristic estrogen-dependent alterations in the female genital tract [4]. E2 is the main estrogen in the human body and is primarily produced in the ovarian follicle, sustaining a production of E2 as high as 700 ␮g daily, depending on the phase of the menstrual cycle [5,6]. Intracellular effects of estrogens are mediated by estrogen receptors (ER) that regulate transcription of target genes through binding to specific DNA target sequences called Estrogen-responsive elements (ERE) [7]. Estrogen receptors play both genomic and non-genomic functions [8], with the magnitude and tissue-specific effects mediated by two distinct ER subtypes: ␣ and ␤, as well as by multiple co-regulators. The activities of an extensive number of ER-interacting proteins allow the regulation of several functionalities by ERs, including the activation and repression of transcription, and the modulation of intracellular signaling pathways and the control of cell cycle [8]. Both ERs subtypes are widely expressed in both genders, with ER-␣ being predominant in the mammary gland and in the uterus and ER␤ having a predominant role in the central nervous system, heart, immune system, urogenital tract, bones, kidneys, and lungs. ER␣ and ␤ are found in the cytoplasm and nucleus, with only 2% of ERs being associated with the cellular membrane [9]. E2 induces the transcription of its own receptors and stimulates the biosynthesis of progesterone receptors, which are required for progesterone effects. In opposition, progesterone and progestin, inhibit the transcription of ER

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when bound to respective receptors, inducing an anti-estrogenic effect [10,11]. The genomic activity of estrogens is mediated by their binding to classical ERs and consequent activation of ERE. A non-genomic activity of estrogens is interceded by their binding to the classic and nonclassical ERs present in the plasma membrane and is mediated through second messengers [12]. After the activation by E2 or estrogen-like compounds, ERs can form ER␣/ER␤ homodimers or heterodimers and bind to ERE in promoters, introns, or 3 untranslated regions of target genes. A G protein-coupled receptor (GPR), GPR30, has been proposed to mediate ER␣- and ER␤-independent signaling pathways induced by E2 [13,14], responding to E2 in the plasma membrane or endoplasmastic reticulum [15]. Also, E2 interacts with G-proteins, the p85 subunit of Phophoinositol-3-kinase (PI3-K), with tyrosine-protein kinase Src and caveolin-1, contributing to regulate PI3K/AKT and mitogen-activated protein kinase (MAPK) [16].

3. Menopause The symptoms associated with menopause are uncomfortable for women and affect their emotional and social life. Most of the symptoms result from hormonal changes, especially from the decline in estrogens [17]. The menopausal transition is initiated by fluctuations in the menstrual cycle, comprising a rise in follicle stimulating hormone (FSH) following a decrease in both estrogen and progesterone. The final menstrual period, medically confirmed after twelve months of amenorrhea [18,19] sets the initial stages of menopause. The transition to menopause is a complex but physiological process usually synergizing with the effects of aging and other social adjustments, contributing to decrease life quality [18]. On average, menopause occurs when women are about 51.4 years old [20]. Women who smoke have an accelerated ovarian aging anticipating menopausal transition by two years [21]. Other conditions may affect the onset of menopause, such the age of menarche, ethnic origin, body mass index and family health history [22]. Menopause can also be induced by chemotherapy [23], and radiation [24], which increase follicular atresia and apoptosis or result from surgery [25], through the mechanical removal of ovaries. Circulating hormones during the menopausal transition were initially thought to decrease in a linear fashion, but circulating FSH concentrations increase progressively during the menopausal transition [26]. This does not occur due to decreased estradiol production, which usually occurs during late menopausal transition [27], but instead due to decreased ovarian inhibin secretion [28]. Inhibin and activin, produced by the granulosa cells in the antral and dominant follicles, are proteins that have a role in the menopausal transition [28,29]. Inhibin A increases during the luteal phase while inhibin B increases during the follicular phase, with both events inhibiting pituitary FSH secretion. In opposition, activins are a class of proteins that stimulate pituitary FSH release [30]. By the late reproductive stage, inhibin B decreases while FSH increases. During the menopause transition, inhibin A concentration declines, while increasing in perimenopausal women. This hormone variation may promote an increase of FSH secretion simultaneous with a decrease in estradiol production (Fig. 2). Similarly to estradiol and FSH, activin and inhibin regulate the menstrual cycle and the menopausal transition [28] (Table 1).


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Fig. 1. Different classes of phytoestrogens. Isoflavones, lignans, coumestans and stilbenes are the different classes of PEs showing chemical structure similar to the main female estrogen, estradiol. These compounds are metabolically active, with the exception of secoisolariciresinol and matairesinol that are first converted to enterodiol and enterolactone by the intestinal flora.

Fig. 2. Mitochondrial effects of phytoestrogens in normal tissues: Phytoestrogens have already been described to affect mitochondrial function. Genistein induces the mitochondrial permeability transition possibly by augmenting ROS production by mitochondrial complex III. Resveratrol inhibits complex I activity in liver and brain mitochondria. Moreover, resveratrol, genistein and quercetin inhibit the enzymatic activity of mitochondrial FoF1-ATPase/ATP synthase. Abbreviation: I, II, III, and IV – mitochondrial respiratory chain complexes; V – FoF1-ATPase/ATP synthase; ANT–Adenine Nucleotide Translocator; Cyp D–Cyclophilin D; MPTP–mitochondrial permeability transition pore; mtDNA–mitochondrial DNA;.

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Table 1 Women’s reproductive life span. Time frame representative of Women’s reproductive life span, beginning with menarche and ending with menopausal transition. The table shows the influence of endocrine hormones on the menstrual cycle (adapted from Refs. [17,40,152]).

Hormones Age Reproductive stage Menstrual cycle

Menarche

Reproductive age

Perimenopause

Posmenopause

Normal FSH, E2 activins and inhibins 9–15 years Low Irregular to regular

Normal FSH, E2, activins and inhibins 16–40 years High Regular

Increasing FSH and activin A and decreasing E2 and inhibin B 41–late 50s Low Irregular

Increasing FSH Low E2 60s and further Absent Absent

Although the main characteristics of menopause are related to hormonal changes in women, a single hormone measurement endpoint is not useful for predicting the menopausal phase due to the large hormone fluctuation during this period [30]. Thus, symptoms that appear during this period characterize the menopausal transition.

of menopause-associated symptoms, a combination of estrogens with synthetic progesterone has been used as the classic hormone replacement therapy (HRT), available and administered since the 1940s [47].

3.1. Menopausal symptoms

4.1. Estradiol-based therapy

Body weight gain, fatigue and hot flashes characterize the menopause transition [18]. Hot flashes are manifested as spontaneous sensations of warmth in the chest, neck and face, usually associated with palpitations, and which result from estrogen withdrawal [31]. Persisting for several years, hot flashes interfere with daily activities or regular sleep and are considered a classical menopausal symptom. Hot flashes compromise the quality of life and health status, being associated with anxiety, irritation, panic, and decreased work efficacy [32]. Hot flashes vary in length and intensity, but the mechanisms responsible are not entirely known. It is possible that reduced estrogen levels induce a decrease in endorphin concentrations in the hypothalamus, increasing the release of norepinephrine and serotonin. Those neurotransmitters lower the set point in the thermoregulatory nucleus, and trigger an inappropriate heat loss [33]. Another possibility is that hot flashes result from a decrease of glucose transporter-1 (GLUT1) expression in the blood–brain barrier (BBB), a consequence of diminishing estradiol levels. Lower expression of GLUT-1 in the BBB results in decreased delivery of glucose to the brain. The lower neurobarrier response to metabolic stimulation during estrogen reduction and a consequent vascular reaction is then observed [34]. Besides hot flashes, other menopausal symptoms, such as vaginal dryness, itching and dyspareunia can also be experienced by women during menopause [35]. Reduced vaginal blood flow and vaginal secretions, alterations in vaginal fluid pH from acid to neutral can also alter women sexual behavior [36]. This mainly occurs since the vaginal epithelium becomes thinner and friable, shortening the vagina, which becomes less elastic [37]. Along with these symptoms, several others are associated with the menopause transition including head and backaches and stress [18]. Certain clinical conditions have also been associated with menopause, such as cardiovascular diseases [38] and osteoporosis [39,40]. The risk of cardiovascular disease markedly increases when women enter menopause [41]. Before that, women have a lower risk than men of the same age due to higher circulating levels of high density proteins (HDL), occurring when estrogen levels are elevated in the woman’s body [42,43]. Increased osteoporosis is often associated with menopausal estrogen deficiency, since this induces a deregulation of bone remodeling, with accelerated bone reabsorption and decreased bone formation [44]. In order to overcome menopausal symptoms, HRT therapy has been administered to menopausal and premenopausal women.

Physiologically, follicles are lost due to follicular atresia. Even if some remain in postmenopausal women, those are less sensitive to gonadotropin stimulation. Postmenopausal decline in ovarian E2 induces a decrease in the negative feedback in the pituitary glands, resulting in the secretion of FSH and luteinizing hormone (LH). Most menopausal symptoms result from estrogen deficiency, simultaneous with high levels of LH or gonadotropin releasing hormone [30]. As referred above, the most common therapeutics administered to women during menopause is HRT [30,48,49]. Both progesterone, produced in the corpus luteum, and progestins act on the uterus endometrium, converting it from a proliferative to a secretory tissue [50]. These hormones are as effective as estrogens in the attenuation of hot flashes [50,51]. Hormone replacement therapy inhibits the aging-related bone loss that occurs during menopause. Women under HRT have a lower risk of vertebral and hip fracture [52], a decreased incidence of cardiovascular diseases [53,54], as well as a reduction of vasomotor symptoms and a delay in the onset of Alzheimer disease [55]. The vasoprotective and the antioxidant effects are also responsible for some beneficial effects of estrogens in the brain. In fact, estrogens have been shown to be potentially preventive against neurodegenerative diseases through multiple mechanisms including reactive oxygen species (ROS) scavenging, up-regulation of antioxidant systems, as well as by preventing the impairment of the mitochondrial electron transport chain [56]. However, some controversies regarding the administration of HRT to menopausal women exist. For years, it was almost a dogma that cardiovascular disease was prevented in women undergoing HRT, which was supported by the beneficial effects of estrogen on metabolic risk factors [57,58]. However, the Women’s Health Initiative (WHI) showed that HRT resulted in an increased incidence of stroke [59] and venous thromboembolism [60]. The results from the previous 2002 WHI study also showed that estrogen-based HRTs has negative effects on post-menopausal women [61], including a significant increase in the incidence of breast cancer, heart diseases, pulmonary embolism and vascular dementia in a group of postmenopausal women aged over 65 years old. In agreement, HRT increases the incidence of endometrial cancer and breast cancer [62], as well as gallbladder [63] and ovarian disease [64]. Results from different sources indicate that the use of HRT needs to be carefully assessed and an analysis of risks and benefits of the therapy should be done by the clinician for each individual woman. Clearly, the possible problems associated with HRT in a sub-population in women may expedite the replacement of estrogens by other safer molecules.

4. Hormone replacement therapy It is estimated that by 2030, 47 million women will be undergoing menopause each year [45,46]. Bearing in mind the burden


5. Phytoestrogens Phytoestrogens, a group of plant-derived chemicals, are a popular alternative to estrogens/progesterone therapy [65]. Due to their similar chemical structure to E2, it is thought that PEs can replace estrogens during HRT. Several studies have focused on their potential clinical use and influence on the regulation of cellular pathways [66]. The interest in the use of PEs stems from epidemiologic studies that suggested a decreased risk of breast cancer, lower incidences of menopausal symptoms and osteoporosis in women from countries with high PEs consumption, namely through soy-based diets [67,68]. Several PEs have in vitro antioxidant properties through hydrogen/electron donation via hydroxyl groups, thus acting as free radical scavengers and inhibiting in vivo the development of coronary heart disease and some types of cancer [69]. Beyond those direct effects in radical scavenging, the expression of ManganeseSuperoxide dismutase (MnSOD) and catalase was also up-regulated by PE in monocytes or PC-12 cells, thus contributing to the observed antioxidant effect [70–72]. 5.1. Phytoestrogens: structure, origin and metabolism Phytoestrogens are classified in four main distinct classes: isoflavones, lignans, coumestans and stilbenes (Fig. 1). Isoflavones, originated from soy and soy derivatives are the most common PEs with genistein and daidzein being the most abundant and studied [73]. This class of PEs may also be found in clover and alfalfa [74]. Lignans are the most prevalent PEs in nature, comprising a large variety of individual structures in plants. Many non-toxic lignans are constituents of human diet, being present in high levels in oilseeds, in flaxseed, in grains such as wheat, rye, and oat and in various types of berries. Both isoflavonoids and lignans are stored in plants predominantly as glycosides in vacuoles [75]. Lignans yield metabolites with estrogen activity such as enterodiol and enterolactone through the metabolism of intestinal bacteria (Fig. 2) Non-metabolized plant lignans can also be found in human urine indicating that they can be absorbed from the intestine as aglycones [76]. Coumestans and stilbenes are less abundant in the diet and thus have also been less well-studied [73]. Coumestrol is a coumestan found in clover and alfalfa sprouts and in lower concentrations in lima bean and sunflower seeds, among other sources [77,78]. Resveratrol is the most studied stilbene, being present in grapes, peanuts and cranberries. That compound is metabolized in the intestine and liver by enzymes as ␤-glucuronidase and sulfatase, however, its non-metabolized form is also active [79]. 5.2. Estrogenic activity Phytoestrogens have a phenolic ring, a prerequisite for the binding to estrogen receptors, a molecular weight similar to E2 and can work as agonists or antagonists of ERs. The cellular effects of PEs are influenced by many factors, including concentration, receptor status, presence or absence of endogenous estrogens, and the target tissue [80]. Phytoestrogens dual performance of estrogenic/anti-estrogenic activity may influence their direct effects on cells. The most popular PE, genistein, is effective as an agonist of both ER for concentrations lower than 10 ␮M, with anti-estrogenic properties observed for higher concentrations [81,82]. Phytoestrogens can bind to either ER␣ or ER␤, although with a higher affinity for ER␤ [83]. The estrogenic potency of PEs varies within the particular group and the tissue in study [84]. The presence of a correctly positioned phenolic ring and the distance between the two opposing phenolic oxygen atoms in isoflavone structure is similar to E2. This similitude allows isoflavones to bind to the ER, effectively displacing E2 [85], which may help to

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Table 2 Estrogenic affinity of phytoestrogens as compared with E2. The estrogenic affinity of PEs for each estrogen receptor is dependent on the tissue and agonist concentration. Despite the fact that there are clear voids in the current knowledge, it is generally accepted that PEs have lower estrogenic affinity than E2, adapted from Refs. [85,87]. Estrogens

ER␣% to E2

ER␤% to E2

Tissue

E2 Genistein Daidzein Coumestrol Resveratrol Enterolactone Enterodiol

100 4 0.1 20 0.01 N.D. N.D.

100 87 0.5 140 0.01 N.D. N.D.

Brain Brain Brain Ovary N.D. N.D.

explain how PEs protect against breast cancer, because ER␤ signaling inhibits mammary cell growth [86]. Nevertheless, it is still not defined whether isoflavones competitively displace estradiol by binding to the primary site in the ER, or whether isoflavones bind to a secondary site in the receptor, altering the binding pocket for E2 [84,85]. The recruitment of co-regulatory molecules may be important in determining the biological function of PEs. Particularly, isoflavones appear to selectively trigger ER␤ transcriptional pathways, leading to gene expression repression. This affinity for ER␤ results in the exposure of activation function-2 (AF-2) on the surface of ER␤, which has a greater affinity for several co-regulators [85]. Phytoestrogens also have differential activity on several ER associated-signaling pathways. For example, Akt phosphorylation is normally downstream from ER␣, being up-regulated by genistein and daidzein in ER-positive breast cancer cell lines, while resveratrol shows an inhibitory effect on the phosphorylation of Akt [87]. Furthermore, resveratrol and daidzein activate Akt in ER-negative cell lines, while genistein inhibits its activation [88]. However, PEs have in general a lower affinity to ER than E2. The affinity of PEs to ER depends on the tissue, and it is still undetermined for several of those compounds. In the brain, the affinity of the majority of PEs to the ER is not yet defined, although genistein has an affinity of 4% and 87% for the ER␣ and ER␤, respectively, while daidzein has an affinity of 0.1% and 0.5% to the same receptors, when compared with E2. On the other hand, the binding affinity of coumestrol is 20% and 140% of E2 respectively, [89] presenting a high estrogenic activity [90]. However, its effects as a hormone-like compound are far from being understood. In ovarian cells, the binding affinity of resveratrol to estrogen receptors is 7000 times lower than E2 [91] (Table 2). Novel insights on a recently discovered estrogen binding protein, GPR30, may help to understand cell responses downstream from ER. The interaction of PEs with GPR30, as well as their binding affinities is still not completely understood. However, it has been described that genistein modulates MAPK activation through binding to GPR30 [92]. Non-ER-mediated effects were also involved in PEs effects. For example, genistein inhibits the activity of tyrosine kinase and DNA topoisomerase and suppressed angiogenesis [93]. The antioxidant effects of PE are also thought to derive from non-ER-mediated effects [94,95]. Coumestrol and daidzein induce prolactin release, phosphorylation of ERKs and JNKs, and a rapid increase of intracellular Ca2+ levels in pituitary tumor cells, a process that is ERs-independent [96]. Moreover, genistein regulates ␤-cell function, insulin secretion and cAMP levels also in an ERindependent mechanism [97]. Beyond PEs estrogenic activity, the role of PEs in mediating or regulating non-genomic effects is now a new focus of research.. 5.3. Biologic effects during menopause The use of PEs as an alternative to HRT resulted from observations that several menopausal-associated symptoms or pathologies and with low circulating estrogen [98] were partly prevented.

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Epidemiological studies show that Asian populations have a lower incidence of prostate cancer in comparison with the Western World, which has been suggested to result from higher consumption of PEs in Asia, and the importance that diet is believed to play in cancer [99]. Moreover, in an epidemiologic study of dietary lignan intake and breast cancer, a higher lignan intake was associated with lower risks of that type of cancer [100]. Relative to menopause-associated symptoms, PEs have shown satisfactory results regarding a decreased incidence of hot flashes and night sweating [101]. In this section, we revise some of the effects of PEs in menopause-related conditions. 5.3.1. Menopausal classic symptoms and phytoestrogens The effect of PEs in the attenuation of hot flashes is still far from being fully determined. However, some studies suggest that isoflavones can relieve vasomotor symptoms: episodes of hot flashes and night sweats were demonstrated to be less frequent and weaker in women with higher consumption of isoflavones [102–105]. The role of many PEs on other previously reported menopausal symptoms is still undetermined. 5.3.2. Cancer Increased incidence of breast and endometrial cancer is associated with menopause, mainly due to HRT [62]. Thus, the effects of PEs on cancer incidence and progression are of critical importance when investigating the potential use of those compounds as a safe and viable alternative to HRT. The effect of PEs on cell cycle regulators and transcription factors is relevant since many novel synthetic agents aimed at inhibiting pathways and proteins up-regulated by ER activation are under development [84]. It is important to emphasize that despite numerous and extensive studies on the mechanisms of PEs, there is no clear evidence whether PEs are chemopreventive or facilitators of carcinogenesis. Several isoflavones have potential anti-tumor effects by modulating genes controlling cell cycle progression. Genistein inhibits the activation of the nuclear factor kappa-light polypeptide gene enhancer in B-cells (NF-␬B), regulating a signaling pathway that is implicated in the balance between cell survival and programmed cell death (apoptosis). Antioxidant and antiangiogenic properties of genistein have also been demonstrated [106–108]. Genistein inhibits human mammary epithelial cell growth, increases the expression of tumor suppressor genes and decreases the expression of two tumor promoting genes: p21 and p16 [109]. In accordance, genistein and daidzein inhibited the proliferation of three different breast cancer cell lines [110]. Genistein promoted the mobilization of copper leading to pro-oxidant signaling and consequent cell death; this is particularly relevant for an anticancer therapy since tumor cells have increased copper content [111]. Controversially, soy-based supplements may decrease the efficacy of breast cancer treatment with aromatase inhibitors [112]. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women [113]. On the other hand, daidzein and its metabolite equol induce apoptosis in MCF-7 breast cancer xenografts in rodents, suggesting its use as a core structure for the design of new drugs for cancer therapy [114]. Although isoflavones have agonistic and antagonistic estrogenic effects, these PEs, similarly to lignans, also induce differentiation and inhibit angiogenesis, cell proliferation, tyrosine kinase, and topoisomerase II, thus preventing tumor growth [115]. High serum enterolactone levels were previously associated with a reduced incidence of breast cancer in healthy women [116]. Enterodiol and enterolactone showed a higher inhibition of MCF-7 breast cancer cell growth than their precursors, secoisolariciresinol and matairesinol [117], suggesting that

the parent compounds are less active in terms of cancer cell cytotoxicity. Resveratrol also inhibits cell proliferation, reduces reactive oxygen species and induces apoptosis through cycle arrest in hepatocellular carcinoma cells [118]. Resveratrol also suppresses human metastatic lung and cervical cancer through the inhibition of NF-kB transactivation [119]. Regarding the anti-cancer therapy of PEs, the type of tumor and host determine the final effect of each specific PE on cancer cells. 5.3.3. Cardiovascular diseases The decrease of E2 levels during menopause has been associated with the development of cardiovascular diseases [41,120]. Several PEs have been demonstrated to be cardioprotective during the transition to menopause, including by reducing levels of cholesterol in plasma [121]. Genistein shows pharmacological cardioprotection after ischemic post-conditioning, involving the activation of the estrogen receptor PI3K/Akt and preservation of mitochondrial function, showing to be at lower concentrations as cardioprotective as E2 [122]. The consumption of soy also decreases the arterial pressure in postmenopausal women, which is accepted to be preventive toward the development of heart disease [123]. Genistein also inhibits the activity of inducible nitric oxide synthase (iNOS) and increases the endothelial form activities in an isoproterenolinduced cardiac hypertrophy model in Wistar rats of 10–12 weeks old [124], resulting in a protective cardiac phenotype. This PE has been also shown to increase the cAMP/PKA pathway in a db/db diabetic mouse model, reducing the vascular inflammation related with diabetes [125]. The consumption of soy may also have a role in delaying atherosclerosis and the risk of cardiovascular diseases that is associated with the estrogen deficiency in menopause [126]. In part due to its antioxidant properties, resveratrol prevented the development of insulin resistance, increased mitochondrial biogenesis and improved vascular function in mice at a dose of 4 g/kg of food consumed [127,128]. 5.3.4. Neurodegenerative diseases Due to estrogen withdrawal, women are vulnerable to neurodegenerative disorders such as Alzheimer’s disease [129,130]. The possible benefits of PEs on the CNS are extensive. The PE alphazearalanol effectively antagonizes beta-amyloid-induced oxidative damage in cultured rat hippocampal neurons [131]. Daidzein treatment resulted in decreased apoptosis in the brains of dgalactose-treated mice, characterized by an increase in Bcl-2 mRNA and a decrease in the expression of the caspase-3, making it a potential candidate for therapy [132]. By increasing the expression of the anti-apoptotic protein Bcl-xL, a high soy diet reduced cell death induced by experimental stroke in adult ovariectomized Sprague-Dawley rats [133]. The therapeutic effects of PEs were also observed on Parkinson’s and Alzheimer’s disease. In a Parkinson’s disease mouse model, genistein prevented the loss of neurons through the increase of Bcl-2 gene expression [134]. In a model of Alzheimer’s disease, genistein prevented the effects of beta amyloid (A␤) plaques, including the increase of inflammatory mediators such as cyclooxygenase 2 (COX-2), iNOS, interleukin 1 beta (IL-1␤) and tumor necrosis factor alpha (TNF␣) [135]. Furthermore, acute genistein treatment has been suggested to be useful in improving memory deficits associated with the loss of ovarian function [136]. 5.3.5. Other therapeutic applications Phytoestrogens also prevents hepatic alterations, which may have a role in menopause-associated complications. Coumestrol presents beneficial effects on lipid and glucose metabolism, independent of its estrogenic activity on HepG2 cell line and in ovariectomized rats [137,138]. Daidzein similarly affords hepatic protection against oxidative damage in a d-galactosamine rat model, mediated by increased SOD activity [139]. An anti-diabetic


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Table 3 Summary of relevant work performed with phytoestrogens in the context of menopause-associated pathologies. Several studies attributed beneficial proprieties to PEs, although few works exist in humans. Thus, in our opinion, further investigations are necessary to evaluate the beneficial of PE consumption for menopausal women.

Isoflavones

In vitro

In vivo

Studies in humans

• Present antioxidant and apoptotic proprieties [106–108]

• Afford cardioprotection and mitochondrial preservation after an ischemic insult [122] • Reduced cell death in a model of stroke [133] and in a Parkinson’s disease model [134] • Anti-diabetic effects [140]

• Decrease of frequency and intensity of hot flashes [103–105]

• Prevent the effects of amyloid plaques in cultured astrocytes [135]

Lignans Coumestans Stilbenes

• Reduce breast cancer cell line growth [117] • Have beneficial effects in glucose and lipid metabolism [137] • Reduces metastatic proprieties in lung and cervical cancer cell lines [119]

• Do not decrease breast epithelial proliferation [113]

• Reduce the incidence of breast cancer [116] • Have beneficial effects in glucose and lipid metabolism [138] • Prevent the development of insulin resistance, increase mitochondrial biogenesis and improve mitochondrial function [127,128]

effect of isoflavones in a type-2 diabetes C57BL/KsJ db/db mouse, in which glucose and lipid metabolism were increased [140].

5.3.6. Phytoestrogens cellular interactions During aging, some physiological functions are decreased in women due to estrogen withdrawal, being T-cell signaling one of them. It was observed that genistein was able to restore the activity of NFkB and JAK3 proteins, thus maintaining T-cell homeostasis [141]. Genistein also delays MAPK activation induced by inflammation. On the other hand, PEs have neuroprotective activity, by having estrogenic activity and by activating MAPK/extracellular signal-regulated kinases (ERK) pathway [92]. Additionally, genistein significantly decreased reactive oxygen species levels and induced the expression of antioxidant enzymes MnSOD and catalase, which were associated with AMP-activated protein kinase (AMPK) and phosphatase and PTEN pathways. The induced expression of catalase, MnSOD, and PTEN were reduced by pre-incubation with a pharmacological inhibitor of AMPK, suggesting that genistein primarily acts on that kinase. Furthermore, PTEN is essential for genistein activity. Thus, the lower incidence of cancer in Asian countries may result, at least in part, from the fact that genistein induces the expression of antioxidant enzymes through AMPK activation and increased PTEN expression [70]. Moreover, some PEs as ASPP 049, a diarylheptanoid isolated from Curcuma comosa Roxb, induce cell proliferation of Wnt target genes through ER ␣ and Akt-dependent activation of ␤-catenin signaling in a osteoblast precursor cell line, which might be important in the context of preventing menopause-related bone loss [142]. In addition, experimental data indicated that the potential cross talk between the non-genomic ER␣ and Wnt/␤-catenin signaling pathways, constituting the major regulatory mechanism. This interaction promotes the down-regulation of osteocyte production of sclerostin, a protein produced in osteocytes and which has anti-anabolic effects on bone formation. Sclerostin suppression, in turn, is a central requirement for load-induced formation and mineralization of the bone matrix. It is therefore reasonable that future strategies for preventing and treating postmenopausal osteoporosis use estrogenic compounds (including PEs) to complement antiresorptive therapy, aimed at preventing further bone loss and possibly even at stimulating the gain of bone mass [143]. The effects of PEs have also been observed in osteoclast differentiation. In fact, similarity to E2, coumestrol decreases RANKL-induced formation of Tartrateresistant acid phosphatase (TRAP)-positive cells and shows a dose dependent inhibition of TRAP activity. Also, coumestrol decreases the expression of calcitonin receptor and Matrix metallopeptidase 9 (MMP9) in RANKL-treated cells and RANKL-induced phosphorylation [144]. Following the same results, isoflavones demonstrated

a significant but modest ability to suppress net bone resorption in postmenopausal women at the doses supplied in a determined time period [145]. The main intracellular interactions of PEs in this context occur through ER receptors. An example is genistein which reduces DNA laddering, nuclear condensation and fragmentation as well as caspase activation, decreasing apoptosis in cortical primary neurons, an effect prevented by the addition of an ER inhibitor [146]. Resveratrol, widely consumed as a food supplement, has been suggested to show some benefits in human health. However, the full range of its actions is not known. It is suggested that resveratrol interacts with transmembranar proteins, modulating cellular membrane organization and thus affecting protein function. Also, resveratrol effects on aging may be mediated by increasing NAD+ content and Sirt 1 activity, which is generally related to an increase of mitochondrial metabolism and antioxidant protection [147,148]. On the other hand, resveratrol also shows anti-cancer activity, which may involve the activation of autophagy, previously described for lung adenocarcinoma [149]. In the same study resveratrol induced an accumulation of intracellular free calcium, activating AMPK, that was reversed by the presence of an AMPK inhibitor and Ethylene glycol tetraacetic acid (EGTA), demonstrating that resveratrol induces cell death though autophagy dependent on calcium/AMPK signaling pathway [149]. In terms of oxidative stress, resveratrol was described to scavenge free radicals and to induce the expression of mitochondrial SOD and increase catalase activity [150]. However, although this relevant but sparse knowledge, the role of PEs in attenuating menopause symptoms is still controversial.

5.3.7. Toxicity of phytoestrogens Despite the generally positive effects of PEs, excessive PEs consumption may lead to adverse health effects. Furthermore, not all PEs improve women’s quality of life during menopause. For this reason, future studies with PEs must help define the safest dietary levels and clarify the mechanism of health risks and/or therapeutic action involved. Interestingly, prenatal exposure to genistein resulted in effects in the progeny. This particular study showed that fetus exposure to genistein affects fetal erythropoiesis and gene expression as well as alters DNA methylation of hematopoietic cells. Pregnant mice, consuming doses of soy below the range of human consumption normalized per weight, showed genistein accumulation in the fetus [151]. In agreement with this work, genistein inhibited testosterone secretion in fetal Leydig cells during early fetal development, suggesting that for concentrations relevant for human consumption, genistein may affect the development and function of the male reproductive system [152,153].

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Furthermore, resveratrol concentrations which were previously shown to have potential anticancer activity and to afford cardiac and antioxidant protection, caused a decrease in the final body weight, increased the levels of creatinine, alkaline phosphatase, alanine aminotransferase and albumin serum levels, and reduced hematocrit and red cell counts. Also, resveratrol increased white cell counts, as well as induced significant renal lesions, including severe nephropathy, when administered by gavage to male and female rats [154]. Moreover, relevant alterations on hepatic gene expression (down-regulation of the hepatic markers CaBP9K and IGFBP1 mRNA) resulting from genistein treatment, again raising a cautionary note on the possible toxic effects of that class of compounds [155]. Phytoestrogens also alter mitochondrial function, even for doses observed in plasma in vivo [156]. Genistein induces the mitochondrial permeability transition through increasing ROS production by mitochondrial complex III [157]. Recently, our group demonstrated that resveratrol inhibits rat liver and brain mitochondrial complex I activity, despite showing antioxidant proprieties for the same concentrations [158]. Resveratrol, genistein and quercetin inhibit the enzymatic activity of mitochondrial FoF1-ATPase/ATP synthase, compromising ATP synthesis in isolated of brain and liver preparations [159] (Fig. 2). Although several studies described the benefits of PEs, their effectiveness and safety is still under debate, especially regarding effects during pregnancy. Since several side effects were already described above, the trans-generational impact of PEs [151–153] is something that should be taken into account. A review of the different studies performed on the biological effects of PEs during menopause is summarized in Table 3.

6. Conclusions The menopausal transition is a gradual endocrinologic continuum that leads to the ending of regular ovulatory cycles due to ovarian senescence and to lower levels of circulating estrogens. Several symptoms that clearly compromise women’s quality of life are associated with the period. To decrease the incidence of these symptoms, HRT has been used by menopausal women, with undesired side effects raising some concerns on the use of this therapy. Thus, the search for safer and equally effective new therapies has been increasing. Epidemiologic studies showed that PEs may be an alternative to estrogen/progestin, which compose HRT. Nevertheless, the toxicity associated with PEs is not completely determined. Although there are already some reports showing their effects on mitochondrial respiratory complexes and on the permeability transition pore, the amount of literature about their benefits and toxic effects is still very scarce. Also, some of the possible “toxicity” described, including increased ROS, may in fact contribute to stimulating stress responses in cells, which will confer a protective phenotype against different pathologies. The line dividing toxicity and pharmacological effect is often too narrow. Further work is clearly necessary before counseling PEs consumption to menopausal and pre-menopausal women, as well as to young women. Although there are some data reporting the reduction of cancer risk by the consumption of PEs [160,161], their use during or after cancer treatment should be carefully addressed and analyzed by physicians, and large-scale studies are needed to conclude whether PEs use during cancer therapy results in anti-neoplastic treatment improvement or rather antagonizes the conventional therapy. Furthermore, an often overlooked aspect of compound toxicity regards the effects of mixtures. It is not known whether the toxicity of an antioneoplastic agent in non-target organs is magnified by PEs simultaneous consumption. A special concern should also be taken during pregnancy since PEs-mediated

effects may be perpetuated through future generations in a still undefined manner. Acknowledgments The work in the authors’ laboratory is supported by the Portuguese Foundation for Science and Technology (FCT) PTDC/AGR-ALI/108326/2008 grant to MSS and PEstC/SAU/LA0001/2013–2014 to CNC. ACM, AMS and VAS are funded by FCT fellowships SFRH/BD/33892/2009, SFRH/BD/76086/2011 and SFRH/BPD/31549/2006, respectively. The authors acknowledge Dr. Paulo J. Oliveira for critically reviewing the manuscript and Filipa S. Carvalho for helping with the figures. We are very thankful to Alexandra Holy for editing the manuscript for English content. The funding agency had no role in the decision to publish or in the content of the manuscript. References [1] T.E. Porter, B.M. Hargis, J.L. Silsby, M.E. el Halawani, Characterization of dissimilar steroid productions by granulosa, theca interna and theca externa cells during follicular maturation in the turkey (Meleagris gallopavo), Gen. Comp. Endocrinol. 84 (1) (1991) 1–8, pii: 0016-6480(91)90058-E. [2] T. Endo, H. Henmi, T. Goto, et al., Effects of estradiol and an aromatase inhibitor on progesterone production in human cultured luteal cells, Gynecol. Endocrinol. 12 (1) (1998) 29–34. [3] A.A. Walf, J.J. Paris, M.E. Rhodes, J.W. Simpkins, C.A. Frye, Divergent mechanisms for trophic actions of estrogens in the brain and peripheral tissues, Brain Res. 1379 (2011) 119–136, http://dx.doi.org/10.1016/j.brainres.2010.11.081, pii: S0006-8993(10)02594-1. [4] S. Nilsson, S. Makela, E. Treuter, et al., Mechanisms of estrogen action, Physiol. Rev. 81 (4) (2001) 1535–1565. [5] S.M. Moenter, A.R. DeFazio, G.R. Pitts, C.S. Nunemaker, Mechanisms underlying episodic gonadotropin-releasing hormone secretion, Front. Neuroendocrinol. 24 (2) (2003) 79–93, pii: S009130220300013X. [6] S. Kumar, K. Lata, S. Mukhopadhyay, T.K. Mukherjee, Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: a perspective, Biochim. Biophys. Acta 1800 (10) (2010) 1127–1135, http://dx.doi.org/10.1016/j.bbagen.2010.04.011, pii: S0304-4165(10)001182. [7] W.J. Welboren, H.G. Stunnenberg, F.C. Sweep, P.N. Span, Identifying estrogen receptor target genes, Mol. Oncol. 1 (2) (2007) 138–143, http://dx.doi.org/10.1016/j.molonc.2007.04.001, pii: S1574-7891(07)000312. [8] J.G. Moggs, G. Orphanides, Estrogen receptors: orchestrators of pleiotropic cellular responses, EMBO Rep. 2 (9) (2001) 775–781, http://dx.doi.org/10.1093/embo-reports/kve185, pii: 2/9/775. [9] J.A. Gustafsson, Novel aspects of estrogen action, J. Soc. Gynecol. Investig. 7 (Suppl. 1) (2000) S8–S9. [10] F. Vignon, S. Bardon, D. Chalbos, H. Rochefort, Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture, J. Clin. Endocrinol. Metab. 56 (6) (1983) 1124–1130. [11] Z.Y. Zheng, V.C. Lin, Anti-estrogenic effect of unliganded progesterone receptor is estrogen-selective in breast cancer cells MCF-7, Cancer Lett. 268 (2) (2008) 202–211, http://dx.doi.org/10.1016/j.canlet.2008.03.040, pii: S03043835(08)00249-8. [12] R. Losel, M. Wehling, Nongenomic actions of steroid hormones, Nat. Rev. Mol. Cell. Biol. 4 (1) (2003) 46–56, http://dx.doi.org/10.1038/nrm1009, pii: nrm1009. [13] C. Carmeci, D.A. Thompson, H.Z. Ring, U. Francke, R.J. Weigel, Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer, Genomics 45 (3) (1997) 607–617, http://dx.doi.org/10.1006/geno.1997.4972, pii: S08887543(97)94972-7. [14] E.J. Filardo, J.A. Quinn, K.I. Bland, A.R. Frackelton Jr., Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF, Mol. Endocrinol. 14 (10) (2000) 1649–1660. [15] A. Pedram, M. Razandi, E.R. Levin, Nature of functional estrogen receptors at the plasma membrane, Mol. Endocrinol. 20 (9) (2006) 1996–2009, http://dx.doi.org/10.1210/me.2005-0525, pii: me.2005-0525. [16] C.M. Klinge, Estrogenic control of mitochondrial function and biogenesis, J. Cell. Biochem. 105 (6) (2008) 1342–1351, http://dx.doi.org/ 10.1002/jcb.21936. [17] M.R. Soules, S. Sherman, E. Parrott, et al., Stages of Reproductive Aging Workshop (STRAW), J. Womens Health Gend. Based Med. 10 (9) (2001) 843–848, http://dx.doi.org/10.1089/152460901753285732. [18] H.D. Nelson, Menopause, Lancet 371 (9614) (2008) 760–770, http://dx.doi.org/10.1016/S0140-6736(08)60346-3, pii: S01406736(08)60346-3.

A.C. Moreira et al. / Journal of Steroid Biochemistry & Molecular Biology 143 (2014) 61–71 [19] W.H. Utian, Ovarian function, therapy-oriented definition of menopause and climacteric, Exp. Gerontol. 29 (3–4) (1994) 245–251. [20] S.M. McKinlay, D.J. Brambilla, J.G. Posner, The normal menopause transition, Maturitas 61 (1–2) (2008) 4–16. [21] S.M. McKinlay, N.L. Bifano, J.B. McKinlay, Smoking and age at menopause in women, Ann. Intern. Med. 103 (3) (1985) 350–356. [22] M.K. Melby, M. Lock, P. Kaufert, Culture and symptom reporting at menopause, Hum. Reprod. Update 11 (5) (2005) 495–512, http://dx.doi.org/10.1093/humupd/dmi018, pii: dmi018. [23] J.L. Shifren, N.E. Avis, Surgical menopause: effects on psychological well-being and sexuality, Menopause 14 (3 Pt 2) (2007) 586–591, http://dx.doi.org/10.1097/gme.0b013e318032c505, pii: 00042192200714071-00007. [24] R. Sakata, Y. Shimizu, M. Soda, et al., Effect of radiation on age at menopause among atomic bomb survivors, Radiat. Res. 176 (6) (2011) 787–795, http://dx.doi.org/10.1667/RR2676.1. [25] M.T. Knobf, “Coming to grips” with chemotherapy-induced premature menopause, Health Care Women Int. 29 (4) (2008) 384–399, http://dx.doi.org/10.1080/07399330701876562, pii: 791928339. [26] H.G. Burger, G.E. Hale, L. Dennerstein, D.M. Robertson, Cycle and hormone changes during perimenopause: the key role of ovarian function, Menopause 15 (4 Pt 1) (2008) 603–612, http://dx.doi.org/10.1097/gme.0b013e318174ea4d. [27] H.G. Burger, E.C. Dudley, J.L. Hopper, et al., The endocrinology of the menopausal transition: a cross-sectional study of a population-based sample, J. Clin. Endocrinol. Metab. 80 (12) (1995) 3537–3545. [28] J.M. Hurwitz, N. Santoro, Inhibins, activins, and follistatin in the aging female and male, Semin. Reprod. Med. 22 (3) (2004) 209–217, http://dx.doi.org/10.1055/s-2004-831896. [29] P.G. Knight, L. Satchell, C. Glister, Intra-ovarian roles of activins and inhibins, Mol. Cell. Endocrinol. 359 (1–2) (2012) 53–65, http://dx.doi.org/10.1016/j.mce.2011.04.024, pii: S0303-7207(11)00287-5. [30] Practice Committee of American Society for Reproductive Medicine, The menopausal transition, Fertil. Steril. 90 (Suppl. 5) (2008) S61–S65, http://dx.doi.org/10.1016/j.fertnstert.2008.08.095, pii: S00150282(08)03719-9. [31] H.D. Nelson, K.K. Vesco, E. Haney, et al., Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis, JAMA 295 (17) (2006) 2057–2071, http://dx.doi.org/10.1001/jama.295.17.2057, pii: 295/17/2057. [32] E. Daly, A. Gray, D. Barlow, K. McPherson, M. Roche, M. Vessey, Measuring the impact of menopausal symptoms on quality of life, Br. Med. J. 307 (6908) (1993) 836–840. [33] T.D. Shanafelt, D.L. Barton, A.A. Adjei, C.L. Loprinzi, Pathophysiology and treatment of hot flashes, Mayo Clin. Proc. 77 (11) (2002) 1207–1218. [34] S.L. Dormire, The potential role of glucose transport changes in hot flash physiology: a hypothesis, Biol. Res. Nurs. 10 (3) (2009) 241–247, http://dx.doi.org/10.1177/1099800408324558, pii: 1099800408324558. [35] M.L. Krychman, Vaginal estrogens for the treatment of dyspareunia, J. Sex. Med. 8 (3) (2011) 666–674, http://dx.doi.org/10.1111/j.1743-6109.2010.02114.x. [36] J.P. Semmens, C.C. Tsai, E.C. Semmens, C.B. Loadholt, Effects of estrogen therapy on vaginal physiology during menopause, Obstet. Gynecol. 66 (1) (1985) 15–18. [37] N.F. Woods, An overview of chronic vaginal atrophy and options for symptom management, Nurs. Womens Health 16 (6) (2012) 482–494, http://dx.doi.org/10.1111/j.1751-486X.2012.01776.x. [38] R. Hutter, J.J. Badimon, V. Fuster, J. Narula, Coronary artery disease in aging women: a menopause of endothelial progenitor cells? Med. Clin. North Am. 96 (1) (2012) 93–102, http://dx.doi.org/10.1016/j.mcna.2012.01.008, pii: S00257125(12)00009-0. [39] G. Crepaldi, S. Maggi, Epidemiologic link between osteoporosis and cardiovascular disease, J. Endocrinol. Invest. 32 (Suppl. 4) (2009) 2–5. [40] ESHRE Capri Workshop Group, Bone fractures after menopause, Hum. Reprod. Update 16 (6) (2010) 761–773, http://dx.doi.org/10.1093/humupd/dmq008, pii: dmq008. [41] P.J. Oliveira, R.A. Carvalho, P. Portincasa, L. Bonfrate, V.A. Sardao, Fatty acid oxidation and cardiovascular risk during menopause: a mitochondrial connection? J. Lipids 2012 (2012) 365798, http://dx.doi.org/10.1155/2012/365798. [42] K.A. Matthews, R.R. Wing, L.H. Kuller, E.N. Meilahn, P. Plantinga, Influence of the perimenopause on cardiovascular risk factors and symptoms of middleaged healthy women, Arch. Intern. Med. 154 (20) (1994) 2349–2355. [43] E.C. van Beresteijn, J.C. Korevaar, P.C. Huijbregts, E.G. Schouten, J. Burema, F.J. Kok, Perimenopausal increase in serum cholesterol: a 10-year longitudinal study, Am. J. Epidemiol. 137 (4) (1993) 383–392. [44] J.C. Gallagher, P.B. Rapuri, G. Haynatzki, J.R. Detter, Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers, J. Clin. Endocrinol. Metab. 87 (11) (2002) 4914–4923. [45] K. Hill, The demography of menopause, Maturitas 23 (2) (1996) 113–127, pii: 0378-5122(95)00968-X. [46] S. Palacios, Advances in hormone replacement therapy: making the menopause manageable, BMC Womens Health 8 (2008) 22, http://dx.doi.org/10.1186/1472-6874-8-22, pii: 1472-6874-8-22. [47] H. Kopera, P.A. van Keep, Development and present state of hormone replacement therapy, Int. J. Clin. Pharmacol. Ther. Toxicol. 29 (10) (1991) 412– 417.

69

[48] J. Deady, Clinical monograph: hormone replacement therapy, J. Manag. Care Pharm. 10 (1) (2004) 33–47, pii: 2004(10)1: 33-47. [49] Practice Committee of American Society for Reproductive Medicine, Estrogen and progestogen therapy in postmenopausal women, Fertil. Steril. 90 (Suppl. 5) (2008) S88–S102, http://dx.doi.org/10.1016/j.fertnstert.2008.08.091, pii: S0015-0282(08)03713-8. [50] H.L. Franco, C.A. Rubel, M.J. Large, et al., Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function, FASEB J. 26 (3) (2012) 1218–1227, http://dx.doi.org/10.1096/fj.11-193334, pii: fj.11-193334. [51] J. Pitkin, V.P. Smetnik, P. Vadasz, M. Mustonen, K. Salminen, S. Ylikangas, Continuous combined hormone replacement therapy relieves climacteric symptoms and improves health-related quality of life in early postmenopausal women, Menopause Int. 13 (3) (2007) 116–123, http://dx.doi.org/10.1258/175404507781605622. [52] E. Barrett-Connor, Hormone replacement therapy, Br. Med. J. 317 (7156) (1998) 457–461. [53] P. Collins, Clinical cardiovascular studies of hormone replacement therapy, Am. J. Cardiol. 90 (1A) (2002) 30F–34F, pii: S0002914901022202. [54] L. Lisabeth, C. Bushnell, Stroke risk in women: the role of menopause and hormone therapy, Lancet Neurol. 11 (1) (2012) 82–91, http://dx.doi.org/10.1016/S1474-4422(11)70269-1, pii: S14744422(11)70269-1. [55] S. Palacios, Current perspectives on the benefits of HRT in menopausal women, Maturitas 33 (Suppl. 1) (1999) S1–S13. [56] J. Nilsen, Estradiol and neurodegenerative oxidative stress, Front. Neuroendocrinol. 29 (4) (2008) 463–475, http://dx.doi.org/10.1016/j.yfrne.2007.12.005, pii: S0091-3022(07)00074-X. [57] U.J. Gaspard, J.M. Gottal, F.A. van den Brule, Postmenopausal changes of lipid and glucose metabolism: a review of their main aspects, Maturitas 21 (3) (1995) 171–178, pii: 037851229500901V. [58] W.B. Kannel, Metabolic risk factors for coronary heart disease in women: perspective from the Framingham Study, Am. Heart J. 114 (2) (1987) 413–419. [59] C. Renoux, S. Dell’Aniello, S. Suissa, Hormone replacement therapy and the risk of venous thromboembolism: a population-based study, J. Thromb. Haemost. 8 (5) (2010) 979–986, http://dx.doi.org/10.1111/j.1538-7836.2010.03839.x, pii: JTH3839. [60] J.C. Stevenson, Hormone replacement therapy and cardiovascular disease revisited, Menopause Int. 15 (2) (2009) 55–57, http://dx.doi.org/10.1258/mi.2009.009018, pii: 15/2/55. [61] J.E. Rossouw, G.L. Anderson, R.L. Prentice, et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial, JAMA 288 (3) (2002) 321–333, pii: joc21036. [62] R.T. Chlebowski, L.H. Kuller, R.L. Prentice, et al., Breast cancer after use of estrogen plus progestin in postmenopausal women, N. Engl. J. Med. 360 (6) (2009) 573–587, http://dx.doi.org/10.1056/NEJMoa0807684, pii: 360/6/573. [63] R.K. Dhiman, Y.K. Chawla, Is there a link between oestrogen therapy and gallbladder disease? Expert Opin. Drug Saf. 5 (1) (2006) 117–129, http://dx.doi.org/10.1517/14740338.5.1.117. [64] M. Argento, P. Hoffman, A.S. Gauchez, Ovarian cancer detection and treatment: current situation and future prospects, Anticancer Res. 28 (5B) (2008) 3135–3138. [65] K. Mahmud, Natural hormone therapy for menopause, Gynecol. Endocrinol. 26 (2) (2010) 81–85, http://dx.doi.org/10.3109/09513590903184134. [66] H.B. Patisaul, W. Jefferson, The pros and cons of phytoestrogens, Front. Neuroendocrinol. 31 (4) (2010) 400–419, http://dx.doi.org/10.1016/j.yfrne.2010.03.003, pii: S0091-3022(10)00025-7. [67] V. Coxam, Phyto-oestrogens and bone health, Proc. Nutr. Soc. 67 (2) (2008) 184–195, http://dx.doi.org/10.1017/S0029665108007027, pii: S0029665108007027. [68] M. Messina, Investigating the optimal soy protein and isoflavone intakes for women: a perspective, Womens Health (Lond. Engl.) 4 (4) (2008) 337–356, http://dx.doi.org/10.2217/17455057.4.4.337. [69] J.H. Mitchell, P.T. Gardner, D.B. McPhail, P.C. Morrice, A.R. Collins, G.G. Duthie, Antioxidant efficacy of phytoestrogens in chemical and biological model systems, Arch. Biochem. Biophys. 360 (1) (1998) 142–148, http://dx.doi.org/10.1006/abbi.1998.0951, pii: S0003-9861(98)90951-1. [70] C.E. Park, H. Yun, E.B. Lee, et al., The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells, J. Med. Food 13 (4) (2010) 815–820, http://dx.doi.org/10.1089/jmf.2009.1359. [71] E.L. Robb, J.A. Stuart, Multiple phytoestrogens inhibit cell growth and confer cytoprotection by inducing manganese superoxide dismutase expression, Phytother. Res. (2013), http://dx.doi.org/10.1002/ptr.4970. [72] I. Yehuda, Z. Madar, A. Szuchman-Sapir, S. Tamir, Glabridin, a phytoestrogen from licorice root, up-regulates manganese superoxide dismutase, catalase and paraoxonase 2 under glucose stress, Phytother. Res. 25 (5) (2011) 659–667, http://dx.doi.org/10.1002/ptr.3318. [73] R.A. Dixon, Phytoestrogens, Annu. Rev. Plant Biol. 55 (2004) 225–261, http://dx.doi.org/10.1146/annurev.arplant.55.031903.141729. [74] S.A. Bingham, C. Atkinson, J. Liggins, L. Bluck, A. Coward, Phytooestrogens: where are we now? Br. J. Nutr. 79 (5) (1998) 393–406, pii: S0007114598000695. [75] H. Adlercreutz, Lignans and human health, Crit. Rev. Clin. Lab. Sci. 44 (5–6) (2007) 483–525, http://dx.doi.org/10.1080/10408360701612942, pii: 783020201.

70


[76] E. Aehle, U. Muller, P.C. Eklund, S.M. Willfor, W. Sippl, B. Drager, Lignans as food constituents with estrogen and antiestrogen activity, Phytochemistry 72 (18) (2011) 2396–2405, http://dx.doi.org/10.1016/j.phytochem.2011.08.013, pii: S0031-9422(11)00379-7. [77] A.A. Franke, L.J. Custer, C.M. Cerna, K. Narala, Rapid HPLC analysis of dietary phytoestrogens from legumes and from human urine, Proc. Soc. Exp. Biol. Med. 208 (1) (1995) 18–26. [78] D.A. Jacob, J.L. Temple, H.B. Patisaul, L.J. Young, E.F. Rissman, Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogen receptor alpha, Exp. Biol. Med. (Maywood) 226 (4) (2001) 301–306. [79] T. Walle, Bioavailability of resveratrol, Ann. N. Y. Acad. Sci. 1215 (2011) 9–15, http://dx.doi.org/10.1111/j.1749-6632.2010.05842.x. [80] K.D. Setchell, Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones, Am. J. Clin. Nutr. 68 (Suppl. 6) (1998) 1333S–1346S. [81] K. Miyazaki, Novel approach for evaluation of estrogenic and antiestrogenic activities of genistein and daidzein using B16 melanoma cells and dendricity assay, Pigment Cell. Res. 17 (4) (2004) 407–412, http://dx.doi.org/10.1111/j.1600-0749.2004.00167.x, pii: PCR167. [82] Z. Sun, L.M. Biela, K.L. Hamilton, K.F. Reardon, Concentrationdependent effects of the soy phytoestrogen genistein on the proteome of cultured cardiomyocytes, J. Proteom. 75 (12) (2012) 3592–3604, http://dx.doi.org/10.1016/j.jprot.2012.04.001, pii: S1874-3919(12)00207-2. [83] M. Barone, S. Tanzi, K. Lofano, et al., Estrogens, phytoestrogens and colorectal neoproliferative lesions, Genes Nutr. 3 (1) (2008) 7–13, http://dx.doi.org/10.1007/s12263-008-0081-6. [84] T. Oseni, R. Patel, J. Pyle, V.C. Jordan, Selective estrogen receptor modulators and phytoestrogens, Planta Med. 74 (13) (2008) 1656–1665, http://dx.doi.org/10.1055/s-0028-1088304. [85] J. An, C. Tzagarakis-Foster, T.C. Scharschmidt, N. Lomri, D.C. Leitman, Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens, J. Biol. Chem. 276 (21) (2001) 17808–17814, http://dx.doi.org/10.1074/jbc.M100953200, pii: [100953200M]. [86] G. Lazennec, D. Bresson, A. Lucas, C. Chauveau, F. Vignon, ER beta inhibits proliferation and invasion of breast cancer cells, Endocrinology 142 (9) (2001) 4120–4130. [87] D. Vergara, P. Simeone, D. Toraldo, et al., Resveratrol downregulates Akt/GSK and ERK signalling pathways in OVCAR-3 ovarian cancer cells, Mol. Biosyst. 8 (4) (2012) 1078–1087, http://dx.doi.org/10.1039/c2mb05486h. [88] D.M. Brownson, N.G. Azios, B.K. Fuqua, S.F. Dharmawardhane, T.J. Mabry, Flavonoid effects relevant to cancer, J. Nutr. 132 (Suppl. 11) (2002), 3482S-9S. [89] S.M. Belcher, A. Zsarnovszky, Estrogenic actions in the brain: estrogen, phytoestrogens, and rapid intracellular signaling mechanisms, J. Pharmacol. Exp. Ther. 299 (2) (2001) 408–414. [90] H. Tinwell, A.R. Soames, J.R. Foster, J. Ashby, Estradiol-type activity of coumestrol in mature and immature ovariectomized rat uterotrophic assays, Environ. Health Perspect. 108 (7) (2000) 631–634, pii: sc271 5 1835. [91] J.L. Bowers, V.V. Tyulmenkov, S.C. Jernigan, C.M. Klinge, Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta, Endocrinology 141 (10) (2000) 3657–3667. [92] L.J. Luo, F. Liu, Z.K. Lin, et al., Genistein regulates the IL-1 beta induced activation of MAPKs in human periodontal ligament cells through G protein-coupled receptor 30, Arch. Biochem. Biophys. 522 (1) (2012) 9–16, http://dx.doi.org/10.1016/j.abb.2012.04.007, pii: S0003-9861(12)00138-5. [93] M.H. Ravindranath, S. Muthugounder, N. Presser, S. Viswanathan, Anticancer therapeutic potential of soy isoflavone, genistein, Adv. Exp. Med. Biol. 546 (2004) 121–165. [94] P.J. Little, R. Getachew, H.B. Rezaei, et al., Genistein inhibits PDGF-stimulated proteoglycan synthesis in vascular smooth muscle without blocking PDGFbeta receptor phosphorylation, Arch. Biochem. Biophys. 525 (1) (2012) 25–31, http://dx.doi.org/10.1016/j.abb.2012.05.025, pii: S0003-9861(12)00236-6. [95] A.L. Ososki, E.J. Kennelly, Phytoestrogens: a review of the present state of research, Phytother. Res. 17 (8) (2003) 845–869, http://dx.doi.org/10.1002/ptr.1364. [96] Y.J. Jeng, M.Y. Kochukov, C.S. Watson, Membrane estrogen receptor-alpha-mediated nongenomic actions of phytoestrogens in GH3/B6/F10 pituitary tumor cells, J. Mol. Signal. 4 (2009) 2, http://dx.doi.org/10.1186/1750-2187-4-2, pii: 1750-2187-4-2. [97] D. Liu, W. Zhen, Z. Yang, J.D. Carter, H. Si, K.A. Reynolds, Genistein acutely stimulates insulin secretion in pancreatic beta-cells through a cAMP-dependent protein kinase pathway, Diabetes 55 (4) (2006) 1043–1050, pii: 55/4/1043. [98] V.B. Gencel, M.M. Benjamin, S.N. Bahou, R.A. Khalil, Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease, Mini Rev. Med. Chem. 12 (2) (2012) 149–174, pii: BSP/MRMC/EPub/270. [99] M. Adjakly, M. Ngollo, J.P. Boiteux, Y.J. Bignon, L. Guy, D. Bernard-Gallon, Genistein and daidzein: different molecular effects on prostate cancer, Anticancer Res. 33 (1) (2013) 39–44, pii: 33/1/39. [100] S.E. McCann, K.C. Hootman, A.M. Weaver, et al., Dietary intakes of total and specific lignans are associated with clinical breast tumor characteristics, J. Nutr. 142 (1) (2012) 91–98, http://dx.doi.org/10.3945/jn.111.147264, pii: jn.111.147264. [101] G. Cheng, B. Wilczek, M. Warner, J.A. Gustafsson, B.M. Landgren, Isoflavone treatment for acute menopausal symptoms, Menopause 14 (3 Pt 1) (2007) 468–473, http://dx.doi.org/10.1097/GME.0b013e31802cc7d0.

[102] K. Taku, M.K. Melby, F. Kronenberg, M.S. Kurzer, M. Messina, Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials, Menopause (2012), http://dx.doi.org/10.1097/gme. 0b013e3182410159. [103] B.H. Jenks, S. Iwashita, Y. Nakagawa, et al., A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency and other menopausal symptoms, J. Womens Health (Larchmt) (2012), http://dx.doi.org/10.1089/jwh.2011.3153. [104] R. Bolanos-Diaz, J.C. Zavala-Gonzales, E. Mezones-Holguin, J. FranciaRomero, Soy extracts versus hormone therapy for reduction of menopausal hot flushes: indirect comparison, Menopause 18 (7) (2011) 825–829, http://dx.doi.org/10.1097/gme.0b013e31820750bc. [105] A. Jacobs, U. Wegewitz, C. Sommerfeld, R. Grossklaus, A. Lampen, Efficacy of isoflavones in relieving vasomotor menopausal symptoms – a systematic review, Mol. Nutr. Food Res. 53 (9) (2009) 1084–1097, http://dx.doi.org/10.1002/mnfr.200800552. [106] M.K. Hagen, A. Ludke, A.S. Araujo, et al., Antioxidant characterization of soy derived products in vitro and the effect of a soy diet on peripheral markers of oxidative stress in a heart disease model, Can. J. Physiol. Pharmacol. 90 (8) (2012) 1095–1103, http://dx.doi.org/10.1139/y2012-028. [107] J. Li, D. Gang, X. Yu, et al., Genistein: the potential for efficacy in rheumatoid arthritis, Clin. Rheumatol. (2013), http://dx.doi.org/10.1007/s10067-012-2148-4. [108] M. Piao, D. Mori, T. Satoh, Y. Sugita, O. Tokunaga, Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the downregulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis, Endothelium 13 (4) (2006) 249–266, http://dx.doi.org/10.1080/10623320600903940, pii: GJ254U880133P681. [109] Y. Li, H. Chen, T.M. Hardy, T.O. Tollefsbol, Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein, PLoS One 8 (1) (2013) e54369, http://dx.doi.org/10.1371/journal.pone.0054369, pii: PONE-D-12-27900. [110] E.J. Choi, G.H. Kim, Antiproliferative activity of daidzein and genistein may be related to ERalpha/c-erbB-2 expression in human breast cancer cells, Mol. Med. Report (2013), http://dx.doi.org/10.3892/mmr.2013.1283. [111] M.F. Ullah, A. Ahmad, H. Zubair, et al., Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species, Mol. Nutr. Food Res. 55 (4) (2011) 553–559, http://dx.doi.org/10.1002/mnfr.201000329. [112] M.B. van Duursen, S.M. Nijmeijer, E.S. de Morree, P.C. de Jong, M. van den Berg, Genistein induces breast cancer-associated aromatase and stimulates estrogen-dependent tumor cell growth in in vitro breast cancer model, Toxicology 289 (2–3) (2011) 67–73, http://dx.doi.org/10.1016/j.tox.2011.07.005, pii: S0300-483X(11)00265-4. [113] S.A. Khan, R.T. Chatterton, N. Michel, et al., Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial, Cancer Prev. Res. (Phila.) 5 (2) (2012) 309–319, http://dx.doi.org/10.1158/1940-6207.CAPR-11-0251, pii: 5/2/309. [114] X. Liu, N. Suzuki, Y.R. Santosh Laxmi, Y. Okamoto, S. Shibutani, Anti-breast cancer potential of daidzein in rodents, Life Sci. 91 (11–12) (2012) 415–419. [115] H. Adlercreutz, Phytoestrogens: epidemiology and a possible role in cancer protection, Environ. Health Perspect. 103 (Suppl. 7) (1995) 103–112. [116] P. Guglielmini, A. Rubagotti, F. Boccardo, Serum enterolactone levels and mortality outcome in women with early breast cancer: a retrospective cohort study, Breast Cancer Res. Treat. 132 (2) (2012) 661–668, http://dx.doi.org/10.1007/s10549-011-1881-8. [117] S. Abarzua, T. Serikawa, M. Szewczyk, D.U. Richter, B. Piechulla, V. Briese, Antiproliferative activity of lignans against the breast carcinoma cell lines MCF 7 and BT 20, Arch. Gynecol. Obstet. 285 (4) (2012) 1145–1151, http://dx.doi.org/10.1007/s00404-011-2120-6. [118] G. Notas, A.P. Nifli, M. Kampa, J. Vercauteren, E. Kouroumalis, E. Castanas, Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation, Biochim. Biophys. Acta 1760 (11) (2006) 1657–1666, http://dx.doi.org/10.1016/j.bbagen.2006.09.010, pii: S0304-4165(06)002868. [119] Y.S. Kim, J.W. Sull, H.J. Sung, Suppressing effect of resveratrol on the migration and invasion of human metastatic lung and cervical cancer cells, Mol. Biol. Rep. 39 (9) (2012) 8709–8716, http://dx.doi.org/10.1007/s11033-012-1728-3. [120] C. Vassalle, A. Mercuri, S. Maffei, Oxidative status and cardiovascular risk in women: keeping pink at heart, World J. Cardiol. 1 (1) (2009) 26–30, http://dx.doi.org/10.4330/wjc.v1.i1.26. [121] W.O. Song, O.K. Chun, I. Hwang, et al., Soy isoflavones as safe functional ingredients, J. Med. Food 10 (4) (2007) 571–580, http://dx.doi.org/10.1089/jmf.2006.0620. [122] R. Tissier, X. Waintraub, N. Couvreur, et al., Pharmacological postconditioning with the phytoestrogen genistein, J. Mol. Cell. Cardiol. 42 (1) (2007) 79–87, http://dx.doi.org/10.1016/j.yjmcc.2006.10.007, pii: S0022-2828(06)009734. [123] S. Carlson, N. Peng, J.K. Prasain, J.M. Wyss, Effects of botanical dietary supplements on cardiovascular, cognitive, and metabolic function in males and females, Gend. Med. 5 Suppl. A (2008) S76–S90, http://dx.doi.org/10.1016/j.genm.2008.03.008, pii: S1550-8579(08)00009-0.

A.C. Moreira et al. / Journal of Steroid Biochemistry & Molecular Biology 143 (2014) 61–71 [124] S.K. Maulik, P. Prabhakar, A.K. Dinda, S. Seth, Genistein prevents isoproterenol-induced cardiac hypertrophy in rats, Can. J. Physiol. Pharmacol. 90 (8) (2012) 1117–1125, http://dx.doi.org/10.1139/y2012-068. [125] P.V. Babu, H. Si, Z. Fu, W. Zhen, D. Liu, Genistein prevents hyperglycemiainduced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice, J. Nutr. 142 (4) (2012) 724–730, http://dx.doi.org/10.3945/jn.111.152322, pii: jn.111.152322. [126] H.A. Hassan, M.A. Abdel-Wahhab, Effect of soybean oil on atherogenic metabolic risks associated with estrogen deficiency in ovariectomized rats: dietary soybean oil modulate atherogenic risks in overiectomized rats, J. Physiol. Biochem. 68 (2) (2012) 247–253, http://dx.doi.org/10.1007/s13105-011-0137-8. [127] J.A. Baur, K.J. Pearson, N.L. Price, et al., Resveratrol improves health and survival of mice on a high-calorie diet, Nature 444 (7117) (2006) 337–342, http://dx.doi.org/10.1038/nature05354, pii: nature05354. [128] M. Lagouge, C. Argmann, Z. Gerhart-Hines, et al., Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell 127 (6) (2006) 1109–1122, http://dx.doi.org/10.1016/j.cell.2006.11.013, pii: S0092-8674(06)01428-0. [129] A.M. Barron, C.J. Pike, Sex hormones, aging, and Alzheimer’s disease, Front. Biosci. (Elite Ed.) 4 (2012) 976–997, pii: 434. [130] A. Grimm, Y.A. Lim, A.G. Mensah-Nyagan, J. Gotz, A. Eckert, Alzheimer’s disease, oestrogen and mitochondria: an ambiguous relationship, Mol. Neurobiol. 46 (1) (2012) 151–160, http://dx.doi.org/10.1007/s12035-012-8281-x. [131] Y.L. Dong, P.P. Zuo, Q. Li, F.H. Liu, S.L. Dai, Q.S. Ge, Protective effects of phytoestrogen alpha-zearalanol on beta amyloid25-35 induced oxidative damage in cultured rat hippocampal neurons, Endocrine 32 (2) (2007) 206–211, http://dx.doi.org/10.1007/s12020-007-9032-z. [132] Z. Mao, Y.L. Zheng, Y.Q. Zhang, et al., The anti-apoptosis effects of daidzein in the brain of d-galactose treated mice, Molecules 12 (7) (2007) 1455–1470, pii:12071455. [133] T. Lovekamp-Swan, M. Glendenning, D.A. Schreihofer, A high soy diet reduces programmed cell death and enhances bcl-xL expression in experimental stroke, Neuroscience 148 (3) (2007) 644–652, http://dx.doi.org/10.1016/j.neuroscience.2007.06.046, pii: S03064522(07)00810-X. [134] L.X. Liu, W.F. Chen, J.X. Xie, M.S. Wong, Neuroprotective effects of genistein on dopaminergic neurons in the mice model of Parkinson’s disease, Neurosci. Res. 60 (2) (2008) 156–161, http://dx.doi.org/10.1016/j.neures.2007.10.005, pii: S0168-0102(07)01816-0. [135] S.L. Valles, P. Dolz-Gaiton, J. Gambini, et al., Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes, Brain Res. 1312 (2010) 138–144, http://dx.doi.org/10.1016/j.brainres.2009.11.044, pii: S0006-8993(09)02498-6. [136] A. Alonso, H. Gonzalez-Pardo, P. Garrido, et al., Acute effects of 17 betaestradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats, Age (Dordr.) 32 (4) (2010) 421–434, http://dx.doi.org/10.1007/s11357-010-9148-6. [137] M. Takahashi, T. Kanayama, T. Yashiro, et al., Effects of coumestrol on lipid and glucose metabolism as a farnesoid X receptor ligand, Biochem. Biophys. Res. Commun. 372 (3) (2008) 395–399, http://dx.doi.org/10.1016/j.bbrc.2008.04.136, pii: S0006-291X(08)00842-5. [138] L. Nogowski, Effects of phytoestrogen-coumestrol on lipid and carbohydrate metabolism in young ovariectomized rats may be independent of its estrogenicity, J. Nutr. Biochem. 10 (11) (1999) 664–669, pii: S09552863(99)00047-9. [139] M.C. Wong, B. Portmann, R. Sherwood, et al., The cytoprotective effect of alpha-tocopherol and daidzein against d-galactosamineinduced oxidative damage in the rat liver, Metabolism 56 (7) (2007) 865–875, http://dx.doi.org/10.1016/j.metabol.2007.01.005, pii: S00260495(07)00057-1. [140] S. Ae Park, M.S. Choi, S.Y. Cho, et al., Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice, Life Sci. 79 (12) (2006) 1207–1213, http://dx.doi.org/10.1016/j.lfs.2006.03.022, pii: S0024-3205(06)00264-5. [141] J.P. Parry, D.D. Taylor, S.T. Nakajima, C. Gercel-Taylor, Genistein reverses diminished T-cell signal transduction, induced by post-menopausal estrogen levels, Am. J. Reprod. Immunol. 61 (1) (2009) 26–33, http://dx.doi.org/10.1111/j.1600-0897.2008.00658.x, pii: AJI658. [142] K. Bhukhai, K. Suksen, N. Bhummaphan, et al., A phytoestrogen diarylheptanoid mediates estrogen receptor/Akt/glycogen synthase kinase 3beta protein-dependent activation of the Wnt/beta-catenin signaling pathway, J. Biol. Chem. 287 (43) (2012) 36168–36178, http://dx.doi.org/10.1074/jbc.M112.344747, pii: M112.344747.

71

[143] R. Sapir-Koren, G. Livshits, Is interaction between age-dependent decline in mechanical stimulation and osteocyte-estrogen receptor levels the culprit for postmenopausal-impaired bone formation? Osteoporos. Int. 24 (6) (2013) 1771–1789, http://dx.doi.org/10.1007/s00198-012-2208-2. [144] S. Kanno, S. Hirano, F. Kayama, Effects of the phytoestrogen coumestrol on RANK-ligand-induced differentiation of osteoclasts, Toxicology 203 (1–3) (2004) 211–220, http://dx.doi.org/10.1016/j.tox.2004.06.015, pii: S0300483X0400335X. [145] C.M. Weaver, B.R. Martin, G.S. Jackson, et al., Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology, J. Clin. Endocrinol. Metab. 94 (10) (2009) 3798–3805, http://dx.doi.org/10.1210/jc.2009-0332, pii: jc.20090332. [146] N.J. Linford, D.M. Dorsa, 17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calciumATPase inhibitor thapsigargin, Steroids 67 (13–14) (2002) 1029–1040, pii: S0039128X02000624. [147] A.R. Neves, M. Lucio, J.L. Lima, S. Reis, Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrane interactions, Curr. Med. Chem. 19 (11) (2012) 1663–1681, pii: CMC-EPUB20120117-009. [148] C. Canto, J. Auwerx, Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol. Rev. 64 (1) (2012) 166–187, http://dx.doi.org/10.1124/pr.110.003905, pii: pr.110.003905. [149] J. Zhang, J. Chiu, H. Zhang, et al., Autophagic cell death induced by resveratrol depends on the Ca(2+)/AMPK/mTOR pathway in A549 cells, Biochem. Pharmacol. 86 (2) (2013) 317–328, http://dx.doi.org/10.1016/j.bcp.2013.05.003, pii: S0006-2952(13)00287-6. [150] T. Bai, D.S. Dong, L. Pei, Resveratrol mitigates isoflurane-induced neuroapoptosis by inhibiting the activation of the Akt-regulated mitochondrial apoptotic signaling pathway, Int. J. Mol. Med. 32 (4) (2013) 819–826, http://dx.doi.org/10.3892/ijmm.2013.1464. [151] K. Vanhees, S. Coort, E.J. Ruijters, R.W. Godschalk, F.J. van Schooten, Barjesteh van Waalwijk, S. van Doorn-Khosrovani, Epigenetics: prenatal exposure to genistein leaves a permanent signature on the hematopoietic lineage, FASEB J. 25 (2) (2011) 797–807, http://dx.doi.org/10.1096/fj.10-172155, pii: fj.10172155. [152] A. Lehraiki, C. Chamaillard, A. Krust, R. Habert, C. Levacher, Genistein impairs early testosterone production in fetal mouse testis via estrogen receptor alpha, Toxicol. In Vitro 25 (8) (2011) 1542–1547, http://dx.doi.org/10.1016/j.tiv.2011.05.017, pii: S0887-2333(11)00153-6. [153] B.J. Lee, E.Y. Jung, Y.W. Yun, et al., Effects of exposure to genistein during pubertal development on the reproductive system of male mice, J. Reprod. Dev. 50 (4) (2004) 399–409, pii: JST.JSTAGE/jrd/50.399. [154] J.A. Crowell, P.J. Korytko, R.L. Morrissey, T.D. Booth, B.S. Levine, Resveratrol-associated renal toxicity, Toxicol. Sci. 82 (2) (2004) 614–619, http://dx.doi.org/10.1093/toxsci/kfh263, pii: kfh263. [155] P. Diel, T. Hertrampf, J. Seibel, U. Laudenbach-Leschowsky, S. Kolba, G. Vollmer, Combinatorial effects of the phytoestrogen genistein and of estradiol in uterus and liver of female Wistar rats, J. Steroid Biochem. Mol. Biol. 102 (1–5) (2006) 60–70, http://dx.doi.org/10.1016/j.jsbmb.2006.09.022, pii: S0960-0760(06)00268-8. [156] J.F. Marier, P. Vachon, A. Gritsas, J. Zhang, J.P. Moreau, M.P. Ducharme, Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model, J. Pharmacol. Exp. Ther. 302 (1) (2002) 369– 373. [157] M. Salvi, A.M. Brunati, G. Clari, A. Toninello, Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore, Biochim. Biophys. Acta 1556 (2–3) (2002) 187–196, pii: S0005272802003614. [158] A.C. Moreira, A.M. Silva, M.S. Santos, V.A. Sardao, Resveratrol affects differently rat liver and brain mitochondrial bioenergetics and oxidative stress in vitro: investigation of the role of gender, Food Chem. Toxicol. 53C (2012) 18–26, http://dx.doi.org/10.1016/j.fct.2012.11.031, pii: S02786915(12)00838-1. [159] J. Zheng, V.D. Ramirez, Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals, Br. J. Pharmacol. 130 (5) (2000) 1115–1123, http://dx.doi.org/10.1038/sj.bjp.0703397. [160] M.B. Schabath, L.M. Hernandez, X. Wu, P.C. Pillow, M.R. Spitz, Dietary phytoestrogens and lung cancer risk, JAMA 294 (12) (2005) 1493–1504, http://dx.doi.org/10.1001/jama.294.12.1493, pii: 294/12/1493. [161] X.O. Shu, Y. Zheng, H. Cai, et al., Soy food intake and breast cancer survival, JAMA 302 (22) (2009) 2437–2443, http://dx.doi.org/ 10.1001/jama.2009.1783, pii: 302/22/2437.

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