Agonists Antagonists

Estrogenic compounds that are rapidly cleared from target tissues are generally referred to as short-acting estrogens and can display both agonist and antagonis-

Short term effects change in function

Intermediate effects

Long term effects adverse endpoint death altered cell cycle steroid rec. binding/inhibition altered hormone levels altered cell proliferation/differentiation abnormal functioning carcinogenic effects decreased reproduction degraded immune system neurological effects prolonged illness

Fig. 4. Overview of (adverse) effects and endpoints due to EACs.

tic properties [9]. When they are administered by pellet implant (assumed constant blood and tissue levels), they act consistently. When administered as single exposures, opposite effects of short-acting estrogens can occur. For example, estriol administered in a continuous fashion, will act as a full agonist because the estrogen receptors are continuously occupied [30,31]. However, in short-term exposures, estriol acts as an antagonist through competitive interaction with E2 for the ER complexes at the nuclear acceptor sites [32] and is capable of stimulating metabolic activity of the human breast cell (MCF-7) in culture [33]. Compared to E2, estriol shows a more rapid loss as it dissociates quicker from the receptor. The degree of antagonism observed with any estrogen antagonist is related to the dissociation constant (Kd) of the hormone from the receptor [34]. Furthermore, steroid derivatives like estriol cyclopentyl ether are able to extend the biological half-life of estrogen and thus are analogous to the hormone implant system [35].

For non-steroidal anti-estrogens like tamoxifen and clomiphene, the relation between the dissociation constant, Kd, and the degree of antagonism does not seem to hold [36,37]. Here the level of antagonism, and even the change to agonistic effects, is dependent on the species, organ, and tissue [37,38]. Also, experimental conditions can determine the effect of a compound. For example, an estrogen antagonist, ICI 164,384, lacked agonist activity in vivo [26] although it has shown agonistic effects in yeast cell experiments [39].

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