Inhibition of Uterine Receptor Binding of Estradiol by Anti-estrogens (Clomiphene and CL-868)

Certain antiuterotrophic agents, such as ethamoxytriphetol, nafoxidine, clomiphene and Parke-Davis CI-628, act by preventing the association of estrogenic hormones with the extranuclear receptor protein of target tissues. These agents have proved of considerable value in estrogen receptor studies by permitting the distinction between specific hormone-receptor interaction and artifacts of nonspecific binding. Examples include evidence that estrogen-receptor interaction plays a role in uterine growth induction, the first indication of a relation between cytosol and nuclear binding, the relation between steroid structure and specific uterine binding invitro and the prediction of response of human breast cancers to adrenalectomy orhypophysectomy.

Section: Estrogen Antagonists In Vitrosupporting

confidence: 76%

The Use of Estrogen Antagonists in Hormone Receptor Studies

Jensen

Jacobson

Smith

et al. 1972

“…As could be shown by Wyss ei al. [13] and Korenman [5], clomiphene anta gonizes the natural oestrogens on the level of oestrogen-specific cytoplasmic or nuclear receptor proteins. In this respect, the ra-isomer possesses a higher receptor affinity than the irons-isomer [5].…”

mentioning

confidence: 99%

Studies on the Anti-Oestrogenic and Oestrogen-Like Action of Clomiphene Citrate. Animal experiments

Schulz¹,

August²,

Gasde³

et al. 1972

The anti-oestrogenic and oestrogen-like potencies of clomiphene citrate are presumably mainly responsible for the mode of action of this synthetic compound in different organs of the female endocrine system. The investigations described in this paper should give more informations about these properties of clomiphene. Therefore the in vivo effect of cis- or trans-clomiphene on some metabolic pathways of the uterine tissue was tested. Studying the influence of cis- or trans-clomiphene on the ³H-oestradiol uptake into uterine tissue in vivo, the cis-isomer indicated the higher anti-oestrogenic effectiveness. In contrast to this observation both isomers were able to imitate biochemical effects of natural oestrogens in the uterus, i.e. the stimulation of the protein- and RNA-synthesizing activity of this organ. These biochemical alterations however, appeared some hours later as compared with 17β-oestradiol. On the base of these results and of experimental data obtained from the literature a model for the mode of action of clomiphene in the female reproductive system is proposed.

“…Most of the antiestrogens inhibit the uptake of labelled estrogen by the estrogen-sensitive target organs [8,10,13,15,17,19] (table I, II). Although the nature of the antiestrogen receptors is not clear, it appears that they are the same as estrogen receptors [19].…”

Section: Mode O F Actionmentioning

confidence: 99%

“…Although the nature of the antiestrogen receptors is not clear, it appears that they are the same as estrogen receptors [19]. The competitive nature of the estrogen-antiestrogen interaction is evident in the inhibition of the estrogeninduced biochemical processes in the uterus, cervix and vagina of rodents [9,11,12,14,18].…”

Section: Mode O F Actionmentioning

confidence: 99%

A Critique on the Evaluation and Mode of Action of Antiestrogens

Sankaran¹,

Prasad²

1972

(1) The ‘true antiestrogens’ are estrogenic and are competitive inhibitors of estrogen action at the estrogen-sensitive target organs. The estrogenicity of a compound needs to be specified with reference to (a) the target tissue, (b) parameter used, (c) route of administration, (d) dose of the compound, (e) time sequence of action. The degree of antiestrogenicity is directly proportional to the, estrogenicity of the compound. The antiestrogenic action of a compound is related to its affinity with the receptor sites in the target organ: (a) compounds which are bound to the receptors for brief periods are weakly estrogenic (DMS, cis-clomiphene), (b) compounds which have greater binding affinity with the receptors in the target organ are strongly estrogenic and antiestrogenic (CN 55, 945–27; trans-clomiphene, DES, MER-25 at high doses). The duration of antiestrogenic action of a compound is related to the duration of its binding with the receptor in the target organ.