Estradiol activity

Estradiol activates a variety of signaling pathways via membrane-associated receptors in many cell types [20]. In neurons, rapid actions of estradiol stimulate translation of a key protein, PSD-95, involved in synapse formation [24],... 

RBA, relative binding affinity % of estradiol activity) ER, estrogen receptor. 

Diethylstilbestrol (DES) was given to pregnant women to prevent miscarriage, until it was found that the drug caused cancer in both the mothers and their female children. DES has estradiol activity even though it is not a steroid. Draw DES in a way that shows that it is structurally similar to estradiol. 

Very Htfle data are available regarding effects of anaboHc steroid implants on the Hpid metaboHsm in growing mminants. Lipogenic enzyme activity and fatty acid synthesis in vitro were elevated in subcutaneous adipose tissue from bulls implanted with estradiol (44), which may account for the increase in fat content of carcasses reported in some studies. TBA implants have no effect on Hpogenesis in intact heifers, and only tend to reduce Hpogenic enzyme activities in ovariectomized heifers (45). 

The two synthetic steroidal estrogens which have attained the greatest degree of therapeutic use are ethinyl estradiol [57-63-6] (EE) (5) and its 3-methyl ether, mestranol [72-33-3]((5). In contrast to the naturally occurring estrone derivatives, these acetylenic analogues are orally active and are the main estrogenic components of combination oral contraceptives (see Contraceptives) and certain estrogen replacement products. 

A stmcturally related series of phenyfiiydrazones resulted ia the selection of compound A-007 [2675-35-6] (DEKK-TEC)(37) for the treatment of hormone-dependent tumors. A-007 is an antiestrogen that, ia contrast to tamoxifen, demonstrated inhibitory activity both ia the presence and absence of estradiol ia ZR-75-1 estrogen-dependent human breast cancer cells, and afforded more protection than tamoxifen ia the 7,12-dimethylbenz[i7]anthracene... 

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

Although estrone and estradiol (26) have both been isolated from human urine, it has recently been shown that it is the latter that is the active compound that binds to the so-called estrogen receptor protein. Reduction of estrone with any of a large number of reducing agents (for example, any of the complex metal hydrides) leads cleanly to estradiol. This high degree of stereoselectivity to afford the product of attack at the alpha side of the molecule is characteristic of many reactions of steroids. 

Although both estrone and estradiol are available for replacement therapy, they suffer the disadvantage of poor activity on oral administration and short duration of action even when administered parenterally, because of ready metabolic disposition. In order to overcome these deficiencies, there was developed a series of esters of estradiol with long-chain fatty acids. These esters are oil-soluble and correspondingly water-insoluble compounds. 

Reaction of estrone with a metal acetylide affords 17a-ethynyl-173-hydroxy-estradiol (etbynylestradiol, 30a EE). This compound is equipotent with estradiol by subcutaneous administration, but it is 15 to 20 times as active when administered orally. Ethynylation of the methyl ether of estradiol analogously affords mestranol (30b), It should be noted that the same factors apply in these reactions as in previously discussed reductions at 17 almost the sole products of these reactions are those which result from attack of reagent from the least hindered a side of the steroid. Ethynylestradiol and mestranol are of special commercial significance since the majority of the oral contraceptives now on sale incorporate one or the other of the compounds as the estrogenic component. 

Diethylstilbestrol (DES) has estrogenic activity even though it is structurally unrelated to steroids. Once used as an additive in animal feed, DES has been implicated as a causative agent in several types of cancer. Show how DES can be drawn so that it is sterically similar to estradiol. 

A major obstacle to the use of naturally occurring estrogens for the purpose of contraception was extensive first-pass hepatic metabolism and hence inactivation of the compounds when given orally. The addition of an ethinyl group at the 17 position made estradiol orally active. Ethinyl estradiol is a potent oral estrogen and... 

The human PR exists as two functionally distinct isoforms PRA and PRB transcribed from two promoters from a single gene. PRA lacks the N-terminal 164 aa and is a 769 aa protein. PRB functions as a transcriptional activator in most cell and promoter contexts. In contrast, PRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of SHR transcriptional activity. Different cofactor interactions were demonstrated for PRA and PRB, probably due to an inhibitory domain within the first 140 aa of PRA, which is masked in PRB. Both PR isoforms however, repress estradiol-induced ER activity when liganded. Several other mRNA isoforms are present in PR-positive tissues such as breast cancer with unknown clinical significance. 

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

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