Disease relevance of estradiol

• Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia [1].
• In concert with these results, we show that MUC1 stimulates ERalpha-mediated transcription and contributes to E2-mediated growth and survival of breast cancer cells [2].
• Using a recently developed technique for isolation of highly purified mammalian osteoclasts, we showed that 17 beta-estradiol (E2) was able to directly inhibit osteoclastic bone resorption [3].
• Ovariectomy prior to E2 treatment failed to modify the occurrence of MCA or pituitary tumors [4].
• P4 is used therapeutically to oppose the effect of E2 during hormone replacement therapy and in the treatment of uterine adenocarcinoma [5].

Psychiatry related information on estradiol

• These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo [6].
• These results indicated that following the initial "priming" of central site(s) with low levels of circulating E2 during diestrus II, rapid elevations in ovarian estrogen secretion between 2300 hr of diestrus II and 0300 hr of proestrus facilitated the neural "trigger" of pituitary LH release during the critical period on proestrus [7].
• To date, studies have demonstrated that estradiol (E2) appears to be a necessary component in the hormonal induction of maternal behavior in rats and other mammals [8].
• These results, which are the first evidence of apoE mRNA localization to microglia in vivo and the control of apoE expression in brain cells by estrogens, are discussed in terms of the possible protective role of E2 in Alzheimer's disease and prior findings that emphasize the expression of apoE mRNA in astrocytes within the brain [9].
• Using Japanese quail (Coturnix coturnix japonica) as an animal model, together with a newly devised procedure for quantifying aggressiveness, we recently showed that aggression is E2-dependent and that individual differences in behavioral intensity are correlated with aromatase in the hypothalamus/preoptic area (HPOA) [10].

High impact information on estradiol

• Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice [11].
• Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland) [1].
• Effects of strain, E2 dose, and the interaction of strain and E2 dose on testes weight and spermatogenesis were all highly significant (P < 0.0001) [12].
• In contrast, mice of the widely used CD-1 line, which has been selected for large litter size, showed little or no inhibition of spermatid maturation even in response to 16 times as much E2 [12].
• Spermatid maturation was eliminated by low doses of E2 in strains such as C57BL/6J and C17/Jls [12].

Chemical compound and disease context of estradiol

• Changes suggestive of squamous cell carcinoma were found in a few BALB/c midvaginal grafts after E2 exposure for 1 mo and in some C57BL midvaginal and FX grafts after E2 and progesterone exposure for 2 mo [13].
• Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells [14].
• EE2 treatment reduced the number and size of altered hepatic foci in N-nitrosodiethylamine-initiated mice, caused weight loss, anestrus, vaginal keratinization, decreased uterine peroxidase activity, and decreased uterine cytosolic estrogen receptor levels [15].
• Transient transfection of cells expressing ER with a vector containing the CAT gene linked to the mouse mammary tumor virus long terminal repeat sequence, which contains response elements for the glucocorticoid receptor but not the ER, showed that E2 was able to inhibit CAT induction by dexamethasone [16].
• In six women with testicular feminization, the mean production rate of E1 was 99 micrograms/24 h, while that of E2 was 77 micrograms/24 h [17].

Biological context of estradiol

• Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ERalpha recruitment site in estrogen-responsive cells [18].
• At concentrations effective for inhibiting bone resorption, E2 also directly induced osteoclast apoptosis in a dose- and time-dependent manner [3].
• The upregulation (i.e., induction) of the C16 alpha-hydroxylation pathway during 17 beta-estradiol (E2) biotransformation has been associated with mammary cell transformation [19].
• CONCLUSION: ER-negative breast cancer cells stably transfected with either a mutant or wild-type ER gene regain hormonal responsiveness; however, E2 inhibits rather than stimulates cell growth [20].
• In addition, the acute response of eNOS to E2 was reconstituted in COS-7 cells cotransfected with wild-type ERalpha and eNOS, but not by transfection with eNOS alone [21].

Anatomical context of estradiol

• A protein (27,000 molecular weight) was previously found in rat Leydig cells after treatment with estradiol (E2) and human chorionic gonadotropin (hCG) in vitro [22].
• In studies of intact ovine endothelial cells, 17beta-estradiol (E2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists [21].
• It was concluded that: 1) the pituitary glands of young female rats were susceptible to E2 treatment but were insensitive in older females, and 2) the occurrence of MCA in female rats appeared to be promoted by elevated PRL levels secreted by E2-induced pituitary tumors [4].
• Even more dramatic in REA heterozygous animals was the loss of down regulation by E2 of genes in the uterus that are normally repressed by estrogen in wild-type animals [23].
• Mouse embryo fibroblasts derived from heterozygous embryos also displayed a greater transcriptional response to E2 [23].

Associations of estradiol with other chemical compounds

• Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E2, and E2 caused rapid ER-dependent activation of MAP kinase [21].
• DMBA treatment also upregulated the ratio of 16 alpha/C2 hydroxylation of E2 leading to increased formation of 16 alpha-OHE1 [19].
• Four groups of 12 male hamsters were treated for 1 month with EE, 15 micrograms per kg per day, or placebo vehicle administered intraperitoneally and fed either a standard diet, 0.8 mg of cholesterol per g of food, or high cholesterol diet, 2.4 mg of cholesterol per g [24].
• We have previously shown that a ligand-dependent interaction between the two AF-containing regions of ER was promoted by E2 and the antiestrogen trans-hydroxytamoxifen (TOT) [25].
• The effect of ethinyl estradiol (EE2) and dexamethasone (Dex) upon plasma renin substrate (PRS) was studied in rats in relation to sexual maturation and pituitary function [26].

Gene context of estradiol

• SHBG levels were 12% higher in parous women, but there was no difference in percentage of free E2 [27].
• As homodimers the two have been recently shown to exhibit distinct transcriptional responses to estradiol (E2), antiestrogens, and coactivators, suggesting that the ER complexes are not functionally equivalent [28].
• TCDD alone or in combination with E increases formation of ubiquitinated forms of ERalpha, and both coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD induces interaction of the AhR with ERalpha in the presence or absence of E [29].
• Mutations of the ERalpha DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation [30].
• In contrast, E does not induce AhR-ERalpha interactions [29].

Analytical, diagnostic and therapeutic context of estradiol

• Neither ovariectomy, AHPrBP, nor E2 treatment had a significant effect on the volume or rate of formation of cortical bone [31].
• Motif-finding algorithms demonstrated that the estrogen response element (ERE) is the most common motif present in these promoters whereas conventional chromatin immunoprecipitation assays showed E2-modulated recruitment of coactivator AIB1 and RNA polymerase II at these loci [32].
• In Fischer rats, after 63 days of E2, the pituitary weight, serum prolactin, and number of microspheres in the AP were 5-, 42-, and 18-fold greater than control values, respectively [33].
• With cells transfected with reporter gene systems, the activation of estrogen response element-luciferase was studied, and using Western blot analysis, the expression of E2-responsive progesterone receptor (PR) and presnelin 2 protein was monitored [34].
• Furthermore, the effect of resveratrol on formation of preneoplastic lesions (induced by 7,12-dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of BALB/c mice placed in organ culture [34].

References