6Estrogen ReceptorsTwo Different Estrogen Receptors Recent studies have revealed the existence of two distinct estrogen receptors in our bodies: ERa and ERb. While they both bind estrogen as well as other agonists and antagonists, the two receptors have distinctly different localizations and concentrations within our body. Structural differences also exist between the two. allowing for a wide range of diverse and complex processes to take place. The following diagram, adapted from the Gustafsson review (1999), shows the distribution of ERa and ERb
7Estrogen Receptors ER-a ER-b (Kuiper et al. 1996) Uterus, testis, pituitary, ovary, epididymis, and adrenal gland.ER-b (Kuiper et al. 1996)brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis.88% identity with rat ER-b; 47% identity with human ER-aMembrane localized ER (Pietras and Szego, 1997)ERa and b differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.
11Estrogen Signaling Hall et al. 2001. J. Biol. Chem., 276: 36869-36872 Fig. 1. The multifaceted mechanisms of estradiol and estrogen receptor signaling. The biological effects of estradiol (E2) are mediated through at least four ER pathways. 1, classical ligand-dependent, E2-ER complexes bind to EREs in target promoters leading to an up- or down-regulation of gene transcription and subsequent tissue responses. 2, ligand-independent. Growth factors (GF) or cyclic adenosine monophosphate (not shown) activate intracellular kinase pathways, leading to phosphorylation (P) and activation of ER at ERE-containing promoters in a ligand-independent manner. 3, ERE-independent, E2-ER complexes alter transcription of genes containing alternative response elements such as AP-1 through association with other DNA-bound transcription factors (Fos/Jun), which tether the activated ER to DNA, resulting in an up-regulation of gene expression. 4, Cell-surface (nongenomic) signaling, E2 activates a putative membrane-associated binding site, possibly a form of ER linked to intracellular signal transduction pathways that generate rapid tissue responses. The roles of coactivators and corepressors in ER signaling (not shown above) are discussed in the first minireview of this series (55).Hall et al J. Biol. Chem., 276:
22Pytoestrogens in humans Fitoestrogeni hanno una attivita’ piu’ debole di quella degli estrogeni circolanti (17-b-estradiol or estrone).Fitoestrogeni possono legarsi alla sex steroid binding protein (SBP) e a-feroprotein (AFP) e circolare.Fitoestrogeni sono coniugati nel fegato (da sulfotransferasi and UDP-glucoronyosyl transferasi), circolano nel plasma ed escreti nelle urine.Livelli di Fitoestrogeni sono piu’ alti nei fluidi dei dotti prostatici e mammari di quelli del plasma.Le urine dei vegetariani possono contenere 1000 volte piu’ Fitoestrogeni che estrogeni totali.Fitoestrogeni hanno effetti inibitori a mM che sono livelli simili alle urine.
23Fitoestrogeni (PEs) della Soia Genistein, daidzein, coumesterol, and equol si legano e transattivano ER a and b (0.1-10mM)Genistetin ha una affinita’ piu’ alta per ERb.Soia PEs influenzano la progressione del ciclo cellulare, crescita e differenziamento. Hanno attivita’ antiossidanti.
24Red wine phytoestrogens: Resveratrol, quercetin, and anthocyanins Antioxidant, anti‑apoptosis, anti‑inflammatory, anti-cancer, and anti‑invasive.Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic ether bond. Increases HDL cholesterol. Inhibits platelet activation.Ameliorates neuronal damage due to ethanol consumption. Probably via antioxidant effect. Minimizes effects of NOS activity by ehtanol. Inhibits ethanol-induced arachidonic acid release and cycloxygenase activity.Anti-ageing role?inhibitory effects on cancer initiation, growth promotion progression and angiogenesis in model systems.The anti‑proliferative activity of resveratrol is mediated by p38-MAPKs via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by oxidized lipoproteins through inhibition of NF-kB and AP-1 pathways.Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER a (+) breast cancer cells.
25Genistein Both estrogenic and anti-estrogenic effects Synonyms: 4',5,7-Trihydroxyisoflavone;Synonyms: 4',5,7-Trihydroxyisoflavone;Synonyms: 4',5,7-Trihydroxyisoflavone;Genistein4',5,7-TrihydroxyisoflavoneBoth estrogenic and anti-estrogenic effectsInhibitor of tyrosine kinases20-fold higher binding affinity for ER-b than ER-a (Makela et al. 1999)Genistein [ ] Synonyms: 4',5,7-Trihydroxyisoflavone;
26Phytoestrogens in Human Health Cancer preventivePost-menopausal supplementPrevention of osteoporosisCardiovascular healthFertilityBreast enhancementReferences: Kurzer, J. Nutr. 133: 1983S-1986S.Benassayag, et al., J. Chromatogr.B 777:
27Cancer preventiveBenefits to human breast and uterine cancer controversial.Genistein can be carcinogenic in uterine cancer at neonatal exposure.Cancer protective in animal studies, especially when exposed during breast development.Isoflavonoids and lignans stimulate proliferation of ER+ breast cancer cells.Inhibit cell growth at high concentrations and in ERa (-) breast cancer cells.Therefore, ER b may have cancer protective effect.Anti-angiogenic effects of genistein, daidzein, and biochanin A may contribute to antitumor activity.Anti-oxidants in vitro and in vivo.
28Post-menopausal therapy In 2002, the Women’s Health Initiative (WHI) trial of estrogen/progestin therapy was halted midtrial due to high incidence of breast cancer and cardiovascular disease.Consumption of 30mg/d soy isoflavones may reduce hot flashes by 30-50%.
29Prevention of osteoporosis Isoflavone intake increases bone mineral density.Can be useful in preventing post-menopausal osteoporosis.Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, Am. J. Clin. Nutr. 78:593S-609S) .
30Cardiovascular health Average intake of 47g/day soy protein results in 9% decrease in total cholesterol,13% decrease in LDL cholesterol, and a trend towards HDL cholesterol.Flavanoids decrease platelet aggregation.Genistein-induced inhibition of growth factor activity can interfere with platelet and thrombin action.
31Effects on fertility (premenopausal) Interferes with menstrual cycle (delay)Reduced LH and FSH and progesterone.Male rodents exposed to PEs in early life: impaired semen quality, congenital malformations, testicular cancer(coumesterol, delay in mating)