Estrogenic Plants: to Prevent Neurodegeneration and Memory Loss and Other Symptoms in Women After Menopause.

Many other plants with demonstrated EA require further characterization include: Adenophora stricta Miq. (Campanulaceae), native to East Asia (China), also known as Sha Shen and Ladybells ( Kim et al., 2008 ); Artemisia vulgaris L. (Asteraceae), often named mugwort, contains the flavonoids eriodictyol and apigenin ( Lee et al., 1998 ); Asplenium trichomanes L. (Aspleniaceae) known as maidenhair spleenwort, it is used to control irregular menses and as an emmenagogue, aborticide, expectorant, anti-cough remedy, and laxative ( Dall'Acqua et al., 2009 ); Hylodesmum podocarpum subsp. oxyphyllum (DC) H. Ohashi and R.R.Mill. syn. Desmodium oxyphyllum (Fabaceae). This plant, also called ticktrefoils, is a medicinal plant from Asia, that is used for breast cancer ( Yoo et al., 2005 ); Maackia amurensis -Rupr (Fabaceae), is a tree also known as Amur maackia ( Yoo et al., 2005 ; Grishchenko et al., 2016 ); Humulus lupulus L. (Cannabaceae) Methanolic plant extracts bind to ERα and ERβ. And it has EA. Numerous studies of the estrogenic properties for hops are attributed to the component 8-prenylnarigenin ( Liu et al., 2001 ). Another study compared the estrogenic effects of hops to other plants of the licorice species ( Glycyrrhiza glabra , G. inflata , and G. uralensis ) ( Hajirahimkhan et al., 2013 ). All extracts showed EA when tested in cultured endometrial cancer cells, MCF-7 cells expressing an ERE directing the expression of the fluorescent reporter luciferase. The authors ordered the plant extracts by decremental EA as follows: H. lupulus > G. uralensis > G. inflata > G. glabra . Liquiritigenin was selective for ERβ, and isoliquiritigenin was equipotent for both ERα/β. 8-Prenylnaringenin showed nanomolar estrogenic RP without ER selectivity ( Hajirahimkhan et al., 2013 ). A recent study identified 8-Prenylapigenin from Glycyrrhiza inflata as an ERβ agonist ( Hajirahimkhan et al., 2018 ).

It is estimated that by 2030, the world population of menopausal and postmenopausal women will be 1.2 billion ( Borrelli and Ernst, 2008 ). A systematic review of the literature and random-effect meta-analyses of several clinical studies showed that surgical menopause at any age was associated with a decline in verbal and semantic memory and information processing speed ( Georgakis et al., 2019 ). As discussed in previous reports, the role of estrogen over cognition became more relevant due to the worldwide increase in female life expectancy. Different ER ligands, including phytoestrogens and synthetic compounds such as tibolone, are under investigation to alleviate or prevent these cognitive deficits. Tibolone has many beneficial effects on the central nervous system ( Pinto-Almazan et al., 2017 ) by mechanisms counteracting the effects of neuroinflammation, oxidative stress, and mitochondrial dysfunction induced by different insults acting on glial cells, including microglia and astrocytes ( González-Giraldo et al., 2018 ; Hidalgo-Lanussa et al., 2018 ; González-Giraldo et al., 2019 ; Martin-Jimenez et al., 2019 ; Osorio et al., 2019 ; Hidalgo-Lanussa et al., 2020 ) Tibolone binds to the ERs and has positive effects diminishing the negative consequences of estrogen deficiency on cognition in ovariectomized (OVX) Sprague–Dawley rats by a mechanism involving the enhancement of both the serotoninergic and cholinergic systems ( Espinosa-Raya et al., 2012 ; Pinto-Almazan et al., 2017 ). Clinical studies: Considering that menopause arrives on average at 50 years of age, women without intervention can spend more than 30 years in a hypoestrogenic state with several global consequences on cognition and mood ( Slaven and Lee, 1997 ; Shilling et al., 2001 ). Sex hormones modulate brain plasticity processes involved in high-order cognitive functions such as learning and memory ( Frick, 2009 ; Henderson and Popat, 2011 ; Frick, 2012 ; Pompili et al., 2012 ; Hamson et al., 2016 ; Korol and Wang, 2018 ). Clinical studies investigated the correlation between the adult levels of sex hormones and the documented differences in spatial and verbal memory abilities among male and female subjects ( Hugdahl et al., 2006 ). HRT with estrogens and progestins reduces postmenopausal symptoms but increases the risk of mammary carcinomas and cardiovascular events. For this reason, plant-derived estrogenic compounds mimicking the effect of sex hormones with a better safety profile are highly regarded ( Wuttke and Seidlova-Wuttke, 2014 ). Although no consensus has been reached ( Kocoska-Maras et al., 2011 ), most clinical studies show that HRT improves cognitive abilities in menopausal women ( Sherwin and Grigorova, 2011 ). One of these studies included 96 non-menopausal control women, 60 women treated with HRT, 56 postmenopausal women, and 41 men. Participants were requested to learn two-word lists. When they learned list 1, they were given either a forget or a remember list 1 cue. When participants had learned list 2 and finished an interference task, they need to write down all items they recalled. Data analysis revealed an effect of sex hormones on learning abilities as follows. Remember-cued control women recalled more list 1 items than HRT users, young men, and postmenopausal women. In forget-cued women, salivary progesterone correlated positively with the recall of items. Salivary 17 β-estradiol did not correlate with the number of recalled items from list one or two in either remember- or forget-cued control women. However, salivary 17 beta-estradiol correlated with item recall in remember-cued postmenopausal women. They concluded that sex hormones do not affect general verbal memory acquisition or consolidation but modulated cue-specific learning and memory recall ( Kerschbaum et al., 2017 ). Another study showed that HRT with estrogen plus progesterone improved speed cognitive processing in women carrying the Apolipoprotein E (APOE) polymorphisms epsilon (ε) 2/ε3, and ε4. However, women receiving HRT but carrying e3/e3 alleles showed worse verbal memory scores in the Montreal Cognitive Assessment test than control subjects ( Bojar et al., 2013 ). The study of the relationship between endogenous levels of sex hormones (estradiol, estrone, progesterone, and free testosterone) and cognitive abilities (verbal episodic memory, executive functions) showed that progesterone concentrations positively correlated with verbal memory and global cognition ( Henderson et al., 2013 ). They also found that the level of sex hormone-binding globulin positively correlated with verbal memory performance ( Henderson et al., 2013 ). Various studies revealed that estrogen and progesterone positively influence verbal memory in females, and this and other cognitive skills in postmenopausal women ( Keenan et al., 2001 ; Maki and Hogervorst, 2003 ; Hogervorst et al., 2009 ; Brown, 2013 ; Doty et al., 2015 ; Pinto-Almazan et al., 2017 ; Moradi et al., 2018 ). Nevertheless, clinical studies by the Women's Health Initiative showed that women who initiated estrogen treatment alone or combined with progestin at older ages (65–79 years of age) presented a higher risk of cognitive decline and dementia ( Rocca et al., 2011 ). This discrepancy can be explained by the window of opportunity hypothesis, suggesting that estrogen's effects will vary depending on age, cause, and stage of menopause. It seems that in women, estrogen treatment is neuroprotective when started early after menopause (50–60 years of age). The authors recommend that women younger than 51 years of age with premature natural menopause should benefit from HRT ( Rocca et al., 2011 ). Based on this evidence, it is reasonable to postulate that estrogen deficiency can be a crucial factor affecting brain function after menopause.

Estrogenic plants contain estrogenic compounds that, according to many studies including from our research groups, have antioxidant and anti-inflammatory activities that can be useful in many conditions that characterize for inflammation and oxidative stress, including neurodegenerative diseases as well as other neurological conditions ( Lanussa et al., 2016 ; Hidalgo-Lanussa et al., 2018 ; Baez-Jurado et al., 2019 ; González-Giraldo et al., 2019 ; Martin-Jimenez et al., 2019 ; Vesga-Jimenez et al., 2019 ; Hidalgo-Lanussa et al., 2020 ). Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger, is used as a food, spice, herbal supplement for its antioxidant, anti-inflammatory and pharmacological activities ( Kiyama, 2020 ). Epidemiological studies indicated that Ginger has beneficial effects on diabetes, metabolic syndrome, hypercholesterolemia, and inflammatory disorders ( Kiyama, 2020 ). Ginger components include monoterpenes (cineole, citral, limonene, and alpha/beta-pinenes), sesquiterpenes (beta-elemene, farnesene, and zerumbone), phenolics compounds (gingerols, [6]-shogaol, [6]-paradol and zingerone), and diarylheptanoids (curcumin). These compounds prevented cell apoptosis, DNA damage, and inflammation by regulating cell signaling, controlling autophagy and cellular metabolism. Ginger-derived phytoestrogens are important bioactive active components modulating essential brain functions. In a previous study, ginger showed EA (RP of 3.7 × 10 –1 ) ( Kim et al., 2008 ). A methanolic extract of the plant effectively induced EA to more than 50% ( Kang et al., 2006 ). An analysis of a raw extract of the aerial parts of Achillea millefolium L. (Asteraceae) has EA when tested in MCF-7 cells transiently expressing ERs. After fractionating the extract, they found EA in a methanol/water fraction. From the phytoestrogens present in this extract, apigenin and luteolin activated ERs, but luteolin activated the ERβ but not the ERα ( Innocenti et al., 2007 ). Female rats treated with acetaminophen and aqueous extracts of A. millefollium (2 g/kg/day) showed increased plasma levels of the toxicity marker lactate dehydrogenase. However, the extracts enhanced the activity of the antioxidant proteins reduced GSH and glutathione S-transferase (GST) in the uterus ( Baggio et al., 2016 ). Furthermore, treatment with A. millefollium extracts inhibited autoimmune encephalomyelitis in mice ( Vazirinejad et al., 2014 ). A clinical study showed that A. millefolium extracts (250–500 mg/day), when administered to 75 patients with multiple sclerosis (MS) for a year, significantly delayed the time to first relapse, reduced the number of lesions, and improved their cognitive abilities ( Ayoobi et al., 2019 ). Reynoutria japonica Houtt. (Polygonaceae), known as Huzhang in China, is an herbaceous perennial plant natural to Eastern Asia, China, and Russia. However, several species also find in Europe and North America ( Peng et al., 2013 ). Reynoutria japonica Houtt. (Polygonaceae) has been used in clinical practice for the treatment of cancer, endotoxic shock, favus, hyperlipemia, infection, inflammation, jaundice, and scald in China and Japan ( Peng et al., 2013 ). More than 67 compounds, including quinones, stilbenes, flavonoids, coumarins, and ligands have been isolated from this plant. Ethanolic extract of R. japonica showed an estrogenic RP (3.28 × 10 –3 ) ( Zhang et al., 2005 ). This plant, known as damiana, oreganillo, or Mexican tea, grows in Bolivia , Brazil , Mexico , and North America. The leaves of T. diffusa contain the monoterpenes 1,8-cineole, p -cymene, alpha and beta-pinene, tetrafilin B, and caffeine . In the branches, also it has the flavonoid gonzalistosin , steroid beta-sitosterol , and t he xacosanol alkanes n -triacontane and tricosan-2-one. The extracts of T. diffusa show antibacterial and antioxidant properties ( Soriano-Melgar Lde et al., 2014 ). Methanolic extract demonstrated a dose-dependent inhibitory effect on aromatase activity (IC 50 = 63.1 mg/ml). From 24 compounds tested, pinocembrin and acacetin were the most potent aromatase inhibitors having IC 50 values of 10.8 and 18.7 mM, respectively. In addition, three compounds from the extracts apigenin 7-glucoside, Z-echinacin, and pinocembrin showed EA ( Zhao et al., 2008 ). Previous studies have shown that T. diffusa has components such as arbutin that inhibit lipid peroxidation and has immunomodulatory and anti-oxidant properties that have proven beneficial for stomach ulcers ( Taha et al., 2012 ). Anti-inflammatory activity has been found for leaf extracts of Turnera subulata found in the Northeastern regions of Brazil ( Souza et al., 2016 ). In the TCM, Cullen corylifolium (L.) Medik. (Fabaceae) is also known as Buguzhi, and is used to reduce inflammatory processes. The study of ethanolic extracts of C. corylifolium , revealed a estrogenic RP of (1.90 × 10 –4 ) ( Zhang et al., 2005 ). The ethanolic extracts of C. corylifolium contained bakuchiol, psoralen, isobavachalcone, isobavachromene, and bavachinin. Also, hexane and chloroform extracts showed EA when tested in a yeast estrogen screen assay. In this assay, ethanol, hexane, chloroform extracts of CC showed EA, and bakuchiol showed similar EA than genistein (10 –6  M). In an ER binding assay, bakuchiol displayed the strongest ER-binding affinity and five times higher affinity for ERα than for ERβ ( Lim et al., 2011 ). Psoralen is the main bioactive compound in the fruits of C. corylifolium. It is used to treat inflammation, bacterial infections (destroying the formation of biofilm), viral infections, and conditions associated with menopause such as osteoporosis ( Ren et al., 2020 ). Psoralen’s anti-osteoporotic effect involve different proteins factors that participate in the bone remodeling such as bone morphogenetic proteins (BMPs), matrix metalloproteinases, peroxisome proliferators-activated receptor-gamma (PPARgamma), as well as signaling cascades including the inositol-requiring enzyme 1 (IRE1)/apoptosis signaling kinase 1 (ASK1)/c-jun N-terminal kinase (JNK), wnt/β-catenin, and the Protein kinase B (Akt)/activator protein-1 (AP-1) pathways ( Ren et al., 2020 ). These signaling factors may help to treat osteoporosis by activating the osteoblast/osteoclast/chondrocyte differentiation process. The anti-inflammatory and neuroprotective effects of psoralen seem to be the result of its interaction with viral polymerase (Pol), and regulating the activation of TNF-α, transforming growth factor β (TGF-β), interleukin (IL) -4/5/6/8/12/13, GATA-3, and AChE ( Ren et al., 2020 ). Curcuma aromatica Salisb. (Zingiberaceae) also known as wild turmeric. An early study found EA in rhizome extracts of this plant with RP of 8.5 × 10 –4 ( Kang et al., 2006 ). Another study investigated the putative estrogenic and/or antiestrogenic activities of several Asiatic medicinal plants. They found that the highest EA (relative to 17 β -estradiol, RP = 1) were in this order: flowers extracts of Pueraria lobata (RP, 7.75 × 10 –3 ), Amomum xanthioid es (1.25 × 10 –3 ), Glycyrrhiza uralensis , Zingiber officinale, Rheum undulatum, Curcuma aromatica, Eriobotrya japonica, Sophora flavescens, Anemarrhena asphodeloides, Polygonum multiflorum, and Pueraria lobata roots (ranging from 9.5 × 10 –4 to 1.0 × 10 –4 ). Prunus persica, Lycoppus lucidus, and Adenophora stricta had lower RP (9.0 × 1 0 –5 to 8.0 × 10 –5 ). Cinnamomum cassia and Prunus persica , showed antiestrogenic effects with RP of 1.14 × 10 –3 and 7.4 × 10 –4 , respectively (tamoxifen RP = 1) ( Kim et al., 2008 ). In addition, Curcuminoids from C. aromatica have neuroprotective activities against oxidative stress. Curcuminoids present in the radix of C. aromatica are neuroprotective against the toxic effects of 24 h-treatment with H 2 O 2 in PC12 cells. The curcumoids increased cell survival, decreased the release of LDH (a measure of cell death), the cellular Ca 2+ , and ROS levels, enhanced the activities of antioxidant proteins such as SOD, catalase (CAT) and GSH, stabilized the mitochondrial membrane potential, and improved PC12 morphology. The chemical analysis showed that diarylheptanoids and sesquiterpenoids are the primary active chemicals in the extracts tested. On the other hand, Curcumin is the main component of Curcuma longa , a Chinese medicinal plant used to alleviate brain disorders, which is neuroprotective and increases the survival of cultured rodent cortical neurons. The protective effects of curcumin were blocked when neurons were pretreated with a tyrosine kinase B (TrkB) antibody, known to inhibit the activity of the brain-derived neurotrophic factor (BDNF). Conversely, treatment with curcumin increased BDNF and phospho-TrkB effects that, in turn, were blocked by ERK and PI3K inhibitors. Curcumin activated ERK, CREB, and AKT, by mechanisms involving MAPK and PI3K. The authors concluded that curcumin beneficial effects might be mediated via the BDNF/TrkB-MAPK/PI-3K-CREB pathway ( Wang et al., 2010 ). Eriobotrya japonica (Thunb.) Lindl. (Rosaceae) commonly known as the Japanese Medlar or loquat. A study reported that methanolic extracts of E. japonica induced an increase of EA (>50%) ( Kang et al., 2006 ). Ethyl acetate fractions of E. japonica showed EA with an RP of 6.1 × 10 –2 (RP E2 = 1.0) ( Kim et al., 2008 ). However, it my be used with caution as seeds, or pips, and young leaves are slightly poisonous because contain little amounts of cyanogenic glycosides such as amygdalin which release cyanide if eaten. However, numerous studies have shown powerful anti-inflammatory effects in different disease conditions. Silver nanoparticles of Eriobotrya japonica AgNPs stimulated phagocytosis and prevent allergies and the authors concluded that E. japonica could be a promising therapy for preventing inflammation, and bacterial infection by enhancing of phagocytosis ( Jabir et al., 2021 ), arthritis ( Kuraoka-Oliveira et al., 2020 ), asthma ( Kim T.-M. et al., 2020 ), intestinal problems, hepatic damage induced by acetaminophen ( Jiang et al., 2017 ), and metabolic syndrome induced by a high fat diet in C57BL/6J mice ( Li F. et al., 2020 ). In the most recent study male mice 7–9 weeks of age were randomly divided into three groups ( n = 6 mice/group). The first treatment group received 250 µl of saline by IP injection, the second received 50 µg LPS via IP and group 3 was pre-treated with AgNPs (1 mg/kg) and then received 50 µg LPS. After 10 h, mice were sacrificed, and blood and peritoneal fluid was taken for analysis of IL-1β and IL-6 levels. The results showed that the AgNPs synthesized using E. japonica leaf extract inhibited the LPS-induced synthesis and the levels of cytokines such as IL-1β and IL-6 ( Jabir et al., 2021 ). Vigna radiata (L.) R.Wilczek (Fabaceae) is known as mung bean sprout, common in the tropics and warm temperature zones and its extracts have shown to increase cell proliferation above the levels induced by estradiol. This proliferation was suppressed by the ER antagonist, ICI 182.780, suggesting that ER signaling pathways are mediating the proliferative effects of V. radiata ( Boue et al., 2003 ). Preclinical studies have investigated anti-inflammatory and antiarthritic activity of V. radiata sprouts in rats. Ethanolic extracts of the sprouts were used to evaluate its antiarthritic activity using rats treated with complete Freund's adjuvant as a model of arthritis. Treatment with ethanolic extracts of V. radiata significantly reduced the biochemical changes induced by the Freund's adjuvant, such as lipid peroxidation, total reduced glutathione, myeloperoxidase and lysosomal enzymes like cathepsin-D, N-acetyl beta-D-glucosaminase and beta-D-glucuronidase. The findings of this study suggest that V. radiata can reduce inflammation in arthritis ( Venkateshwarlu et al., 2016 ). Further studies are required to investigate its effects in other inflammatory conditions. Wurfbainia villosa var. Xanthioides (Wall. ex Baker) Skornick. and A.D.Poulsen, commonly known as bastard cardamom and Malabar Cardamom, is a medicinal plant native to Indonesia that is used to treat spleen and stomach diseases in China ( An et al., 2020 ). Butanolic fractions of W. villosa var. xanthioides showed EA with a relative potency of 6.6 × 10 –2 (RP of E2 = 1.0) ( Kim et al., 2008 ). Also, methanolic extract of this plant effectively induced a 50% increase in EA ( Kang et al., 2006 ). The herbal mix named CG (plus) contains Artemisia gmelinii Weber ex Stechm. (syn, Artemisia iwayomogi Kitamura), W. villosa and Salvia miltiorrhiza Bunge . The effect of CG (plus) on stress for immobilization (IS) was recently assessed in mice. Male BALB/c mice were daily treated with different doses of aqueous extracts of CG (plus) (0–200 mg/kg) for 5 days. On the last day, mice were subjected to IS for 6 h. Stress increased corticosterone levels, adrenaline, cytokines, and the enzyme markers of hepatic injury (ALT and AST) in serum. The mix CG (plus) significantly prevented the effects of stress ( Kim H.-G. et al., 2020 ). Iris domestica (L.) Goldblatt & Mabb. syn Belamcanda chinensis (Iridaceae) commonly known as Blackberry Lilly. The ethanolic extract of I. domestica showed EA with a RP of (1.26 × 10 –4 ) ( Zhang et al., 2005 ). Isoflavonoids obtained from a methanolic extract of I. domestica rhizomes inhibited mutagenesis when tested in the Ames test and have antioxidant effects. The isoflavonoids reduced transition-metal ions and prevented the peroxidation of polyunsaturated fatty acids. The isoflavones, identified included the glycosides tectoridin and iridin and the aglycones irigenin, tectorigenin, and 5,6,7,3′-tetrahydroxy-4′-methoxyisoflavone ( Wozniak et al., 2010 ). Senna obtusifolia (L.) H.S.Irwin and Barneby (syn. Cassia obtusifolia L.) (Fabaceae) is commonly known as American sicklepod. S. obtusifolia is a weed that grows in the world's tropical and subtropical regions, even when the environmental conditions are unfavorable. This plant has been investigated as a laxative and sexual stimulant in male rats ( Ajayi et al., 2014 ). Ethanolic extracts of S. obtusifolia have shown estrogenic RP of 3.49 × 10 –4 ( Zhang et al., 2005 ). However, its toxic effects observed in cattle and mice discouraged its use as a medicinal plant ( Furlan et al., 2014 ; Ana Maria et al., 2019 ). A different study investigated the effects of Aurantio-obtusin, an anthraquinone isolated from dried seeds of S. obtusifolia and Cassia tora L. (syn. Senna tora). Aurantio-obtusin was tested as an anti-inflammatory compound on lipopolysaccharide- (LPS)-induced inflammation in RAW264.7 cells. ELISA and quantitative real-time PCR (qRT-PCR) assays revealed that this compound significantly decreased the production of NO and PGE 2 by inhibiting the expression of COX-2 and iNOS, as well as the cytokines TNF-α, and IL-6. Aurantio-obtusin showed anti-inflammatory effects via the inhibition of NFκB in RAW264.7 cells. These results suggested that this compound could have therapeutic value against inflammatory diseases. Medicago sativa L. (Fabaceae) is commonly known as alfalfa sprout. M. sativa extracts induce more cell proliferative effects than estradiol. The estrogen receptor antagonist ICI 182,780 (Fulvestrant) suppressed the cell proliferation induced by the extracts, suggesting that ERs were involved ( Boue et al., 2003 ). Moreover, the phytoestrogens present in these extracts exhibited selectivity toward ERβ ( Boue et al., 2003 ). Also a recent study showed that Alfalfa extracts have dose-dependent beneficial effect on nicotine-induced oxidative damage and neuroinflammation in the brain as well as reducing anxiety ( Raeeszadeh et al., 2021 ). In this study the authors investigated the effect of the hydroalcoholic extract of M. sativa on brain damage and anxiety behavior in male Wistar rats exposed to nicotine. Rats were randomly divided into six treatment (T) groups: T1 and T2 were subcutaneously injected with 250 and 500 mg/kg alfalfa extract, respectively, T3 and T4 groups where animals were injected subcutaneously with 0.2 mg/kg nicotine and 250 and 500 mg/kg alfalfa extract, and T5 group was injected with 0.2 mg/kg nicotine. After treatments, the serum levels of the cytokines TCA, IL-1, and TNFα and oxidative stress-defensive factors such as gluthation (GPx, SOD, total antioxidant capacity (TAC), and MDA) in the brain were assayed. The time and number of entrances in the open arm significantly decreased in the treated groups in a dose-depended manner. Oxidative stress parameters were higher in the nicotine -treated rats and lower in the rats treated with 500 mg/kg alfalfa extracts (T2). Nicotine increased the levels of the cytokines TNFα and IL-1 in the T5 group when compared to the other groups. More importantly, treatment with the alfalfa extracts increased the levels of the antioxidant factors GPx and SOD and decreased the number of necrotic neurons and gliosis in the nicotine-treated rats ( Raeeszadeh et al., 2021 ). Phaseolus vulgaris L.(Fabaceae) is also known as green bean or red kidney bean ( Boue et al., 2011 ; de Lima et al., 2014 ). P. vulgaris produces phytoalexins (isoflavones) under stress conditions such as wounding and/or insect damage. Thus to induce the expression of flavonoids, the components of methanolic extracts of red kidney bean that were treated with the fungus Aspergillus sojae, and untreated controls plants were tested for estrogenic activity using an ERE luciferase reporter assay ( Boue et al., 2011 ). The estrogenic activities of the phytoalexins kievitone and phaseollin were isolated from fungus-treated red kidney bean extracts and analyzed for EA using ERα and ERβ binding and ERE luciferase and cell proliferation assays in MCF-7 and HEK 293 cells. These phytoalexins stimulated MCF-7 cell proliferation and Kievitone showed a higher binding affinity to ERα and Phaseollin to ERβ. Although phaseollin displayed attenuation of ER transactivation in the ERE luciferase assay in MCF-7 cells, both phytoalexins attenuated the effects of E2 in an MCF-7 cell survival assay showing estrogenic and antiestrogenic activities ( Boue et al., 2011 ). The green bean extracts were more effective in inducing cell proliferation than estradiol and exhibited a preferential affinity for ERβ. The proliferative effects were due to its estrogenic effects as it was suppressed by ICI 182,780 ( Boue et al., 2011 ). P. vulgaris has shown antioxidant activity in both cell and animal studies ( Venkateswaran et al., 2002 ; Venkateswaran and Pari, 2002 ; Ampofo and Ngadi, 2020 ). One recent study, investigated phenolic compounds, and antioxidant activity, of different species of the genus Phaseolus. The species closest to each other in terms of essential amino acid content were P. polyanthus with P. vulgaris and P. lunatus with P. coccineus . Previous studies show a positive correlation between antioxidant activity and flavonoids, anthocyanins, and lectins. Significant differences in the content of phenolic compounds have been found among the bean species. No obstant, in addition to P. vulgaris , other species such as P. coccineus and P. lunatus have high antioxidant potential ( Alcazar-Valle et al., 2020 ). Pueraria montana var. lobata (Willd.) Maesen and S.M.Almeida ex Sanjappa and Predeep (Fabaceae), also known as kudzu, is a perennial leguminous vine used as an herbal medicine in Asia, containing flavonoids that are concentrated in its root ( Eom et al., 2018 ). Methanolic extract of flowers of P. lobata increased the EA > 50%, but roots only showed moderate EA ( Kang et al., 2006 ). Extracts of kudzu roots induced cell proliferation by a mechanism involving ER as it was suppressed by the antagonist, ICI 182,780 ( Boue et al., 2003 ). Ethanolic extracts of Pueraria lobata showed an estrogenic RP of (6.17 × 10 –5 ) ( Zhang et al., 2005 ) . In another study, 17β-estradiol showed EA with an EC 50 = 0.205 ± 0.025 ng/ml (RP = 100) and methanolic extracts of flowers and stem of P. montana var. lobata showed EA with EC 50 values of 8.6–1.0 μg/ml, respectively ( Yoo et al., 2005 ). A study that used peritoneal macrophages isolated from BALB/c mice and cells activation with lipopolysaccharide (LPS) or LPS plus interferon (IFN)-gamma revealed that kudzu leaf and its principal active compound robinin (kaempferol-3-O-robinoside-7-O-rhanmoside) have anti-inflammatory activity. The extract inhibited the macrophage synthesis of the inflammatory factors iNOS, COX-2, TNFα, and IL-6. Kudzu extracts decreased LPS-induced activation of (JNK and TANK-binding kinase 1 (TBK1). Also, kudzu extract inhibited LPS/IFN-gamma-induced expression of the signal transducer and activator of transcription 1 (STAT1). Robinin decreased iNOS protein involving modulation of JNK and STAT1 activation. But without any impact on other inflammatory markers such as NFκB ( Eom et al., 2018 ).

The deficit of estrogen is involved in the development or progression of various types of autoimmune diseases, cancer (breast, colorectal, endometrium, ovary, prostate), cardiovascular diseases, osteoporosis, obesity, insulin resistance, and neurodegenerative diseases and mood disorders. The deficit in sex hormones such as estrogen negatively impacts the cognitive abilities, general health, and consequently the quality of life of millions of persons around the world. HRT positively impacts cognitive abilities and immune function, but its benefits seem to be restricted to the early stages of menopause. After menopause, HRT with estrogens combined with progestins has shown beneficial effects on climacteric symptoms and osteoporosis in the bone and on body weight. However, it increases the risk of mammary carcinomas and cardiovascular diseases. Consequently, plant-derived alternatives are currently investigated. The advancement of our understanding of the molecular mechanisms underlying the effects of plant-derived estrogenic compounds will facilitate the discovery of new therapies to counteract the adverse effects of a deficit of estrogen in the brain. Interestingly, many plants used in traditional medicine have shown estrogenic activity that is concurrent with antioxidant, antiproliferative, and anti-inflammatory activities. The discovery of estrogenic compounds from medicinal plants with lower side effects should permit to improve the cognitive abilities in women affected by menopause and other conditions inducing oxidative stress and neurodegeneration without the side effects elicited by actual HRT. Recently encouraging clinical results with a combination of herbs have shown to be effective and safe in decreasing menopause symptoms ( Rattanatantikul et al., 2020 ). Also, phytoestrogens and their metabolites from medicinal plants have been shown to mimic the benefits of endogenous estrogens, and estrogen-based therapies are considered promising approaches for preventing the onset and progression of neurodegenerative disorders ( Bustamante-Barrientos et al., 2021 ). Though, xenoestrogens derived from plastic polycarbonates, such as water bottles and varnish coating in food cans, can alter estrogen-mediated signaling pathways inducing a negative effect on health. It may be required to counteract the estrogen deficit in a more holistic approach comprising an adequate diet containing natural estrogenic compounds, body and mental exercise practices that promote neurogenesis, a more ecologically friendly way of life, and adequate social and spiritual support systems to decrease the effects of stress. On the other hand, the explosive development of new genetic therapies may permit the modulation of specific estrogenic receptors in the brain, bones, and other tissues without increasing the risk of disease while preventing the pathological effects of lower sex hormones' levels.

Sex hormones such as androgens and estrogens significantly influence behavior ( Hamson et al., 2016 ) and support learning and memory ( Andreano and Cahill, 2009 ; Munro et al., 2012 ; Colciago et al., 2015 ; Kerschbaum et al., 2017 ). The effects of sex hormones on cognition may explain the differences in cognitive abilities among sexes. For example, typically, women have superior verbal memory and are better at recalling and associating words from a spoken list than men ( Munro et al., 2012 ). Experimental and epidemiological studies suggest that female sex hormones are neuroprotective, preventing cognitive decline during aging. The discovery that brain regions involved in learning and memory, such as the hippocampus and prefrontal cortex, differed in structure and function between sexes suggested that sex hormones played a role in cognition ( Kapur et al., 1995 ; Gasbarri et al., 2012 ; Pompili et al., 2012 ). Sex hormones influence aging ( Boss et al., 2014 ) and the incidence, progression, and severity of symptoms in psychiatric disorders ( Xing et al., 2013 ). One interesting potential beneficial effect of estrogens in the brain is to prevent the deterioration of cognitive abilities during aging. Likewise, estrogenic compounds' study revealed a central role of the cerebral estrogen receptors (ER)α and ERβ signaling on cognitive abilities ( Baez-Jurado et al., 2019 ). These receptors have differential expression in the body's tissues and cells. They can have selective effects on different tissues. Most phytoestrogens are full ERβ agonists and weak ligands of the ERα ( Gencel et al., 2012 ; Martinkovich et al., 2014 ). Estrogenic compounds support cognitive abilities by a mechanism involving the ERα ( Tang S.-S. et al., 2018 ; Mitchnick et al., 2019 ). This receptor, acting as a transcription factor, controls gene expression in brain regions playing a vital role in learning and memory, such as the hippocampus ( Spencer-Segal et al., 2012 ; Frick et al., 2018 ; Tang et al., 2019 ). Also, ERs promote neuroregeneration after traumatic brain injury by stimulating astrocytes' neuroprotective effects ( Martin-Jimenez et al., 2019 ). There is abundant evidence on the therapeutic impact of estrogenic compounds and the molecular mechanisms underlying their beneficial effects diminishing inflammation, oxidative stress, and neuronal loss after menopause. These benefits may also account for their positive impact alleviating the cognitive deficits in animal models of two leading types of dementia; Alzheimer’s disease (AD) and Parkinson’s disease (PD) ( Figure 1 ). Tibolone (7-α, 17- α-17-hydroxy-7-methyl-19-norpregn-5 [10]-en-20-ψn-3-one) an estrogenic synthetic drug used as Hormone replacement therapy (HRT), is neuroprotective against the neurotoxic effects of palmitic acid in the brain by protecting astrocytes from inflammation by a mechanism involving the ERβ In experimental models of inflammation induced by a high-fat diet ( González-Giraldo et al., 2018 ; Hidalgo-Lanussa et al., 2018 ; González-Giraldo et al., 2019 ; Martin-Jimenez et al., 2019 ; Hidalgo-Lanussa et al., 2020 ). On the other hand, the phytoestrogens, also called natural selective estrogen receptor modulators (SERMs), act as agonists or antagonists for ERs. They have different effects on different tissues and cells. The phytoestrogens have structural similarity with 17-β estradiol, showing both agonist and antagonist effects on the ERα and ERβ ( Rietjens et al., 2017 ). Mechanism of action of estrogenic plants to prevent neurodegeneration and memory loss and other symptoms in women after menopause. A comprehensive review of pertinent published literature on estrogenic plants using the scientific databases SCOPUS, PubMed, and Science Direct was done. The revision emphasized plants and compounds with beneficial effects against oxidative stress, inflammation, cell viability, and memory loss in cell and in vivo studies of AD and PD. Only plants with scientific evidence of estrogenic activity were included.