Regulation of Prolactin Synthesis in Vitro by Estrogenic and Antiestrogenic Derivatives of Estradiol and Estrone*

Abstract

The estrogenic and antiestrogenic activities of derivatives of estradiol and estrone were determined in vitro using the ability of primary cultures of immature rat pituitary cells to synthesize PRL. Estradiol derivatives were the most potent estrogens in the assay. Large ethinyl substitutions in the 17 alpha position generally caused a decrease in estrogenic potency (up to 1000-fold). The 3 phenolic hydroxyl was important, but not essential, for the estrogenic activity of the estradiol molecule. Estratriene was approximately 1000 times less potent than estradiol. However, significant estrogenic activity was observed with the compound anordin (EC50, 8 x 10(-9) M), which could potentially be converted to a dihydroxylated derivative but without an aromatic A ring. Similarly, the steroid androst-5-ene-3,17-diol was weakly estrogenic (EC50, 3 x 10(-8) M). Steriods with a ketone in the A and D rings were generally inactive as estrogens and antiestrogens. Estradiol derivatives with 17 beta amines were only weak estrogens. Estrone derivatives were less active than the corresponding estradiol derivatives. 4-Nitromethoxyestrone exhibited weak antiestrogenic properties; however, 4-nitroestrone and methoxyestrone were both estrogens. The reason for the antiestrogenic properties of 4-nitromethoxyestrone is obscure, as the compound does not have structural features similar to those of known nonsteroidal antiestrogens. Minor alterations to the estradiol molecule at the 11 beta (OH) or 6 (ketone) position had little effect on estrogenic potency; however, large substitutions at the 11 beta (RU 39,411) or 7 alpha (ICI 164384) position produced antiestrogenic compounds. RU 39,411 was approximately 10 times more active as an antiestrogen than 4-hydroxytamoxifen, whereas ICI 164,384 was approximately 10 times less active than 4-hydroxytamoxifen. A series of hypothetical models is proposed that could explain the antiestrogenic properties of RU 39,411 and ICI 164,384 by an interaction with the estrogen receptor steroid-binding site.

Endocrine factors and ovarian follicles are influenced by body condition and somatotropin in postpartum beef cows1,2

“…Concentrations of prolactin were greater in the follicular fluid of normal, nonatretic follicles compared with atretic follicles (Lebedeva et al, 1998). Estrogens stimulate synthesis of pituitary prolactin (Jordan and Koch, 1989), and follicular prolactin paralleled follicular estrogen after PGF 2α administration in beef heifers (Wise and Maurer, 1994). Concentrations of prolactin were influenced by BC and luteal status of cows in the current experiment.…”

Regulation of Low-Density Lipoprotein Receptor Activity by Estrogens and Phytoestrogens in a HepG2 Cell Model

“…Studies examining estrogenicity have found that 17ß-estradiol is up to 10 times more potent than estriol [23]. The hydrogen bond interactions between amino acids within the estrogen receptor structure and the phenolic hydroxyl group present on 17ß-estradiol play a vital role in the function of the estrogen receptor [24], however the phenolic hydroxyl group can also confer antioxidant activity to 17ß-estradiol.…”

The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy

“…Studies in vitro reflect constant concentrations to create knowledge of intrinsic efficacy of the complex specifically. The modulation of the prolactin gene through rigorous SAR (Jordan et al , 1984, Jordan et al , 1986, Jordan, 1987, Jordan and Koch, 1989, Lieberman et al , 1983a, Lieberman et al , 1983b, Robinson et al , 1988, Tate et al , 1984b) created the “crocodile model” of antiestrogen action (Jordan, 1987) with the antiestrogenic side chain predicted to interact at an “antiestrogenic region” of the ligand-binding domain. The side chain prevented the “jaws” closing over the ligand thereby preventing activation of the ER complex (Jordan, 1984, Lieberman et al , 1983b, Tate et al , 1984a).…”