Agonist and Antagonist Activity of en-Clomiphene Upon Oestrogen-Mediated Events in the Uterus, Pituitary Gland and Brain of the Rat

Abstract

The oestrogen agonist and antagonist activity of a single dose of en-clomiphene (0.5--50 mg/kg) was studied in peripheral and brain tissue in the 3 week ovariectomized rat. 17 beta-Oestradiol benzoate (100 microgram/kg) or vehicle was injected 24 h after en-clomiphene administration and data collected at 72 h. En-clomiphene produced a dose-related (agonist) fall in body weight and food intake. Agonist action was not observed upon sexual receptivity and prolactin secretion; oestrogen antagonism of these parameters was only seen at the higher doses. The effects of en-clomiphene upon serum LH and FSH were complex, both agonist and antagonist activity being demonstrated in the absence and presence of oestrogen. En-clomiphene was uterotrophic at all doses tested; however, oestrogen antagonism was only seen at the higher doses. Inhibition of the accumulation of uterine luminal fluid at the higher doses of en-clomiphene was a sensitive index of oestrogen antagonism. The results are discussed in relation to previous studies of the effects of en-clomiphene on oestrogen receptors. With the exception of the antagonism of oestrogen-induced sexual receptivity no correlation could be made between biological activity and the status of oestrogen receptors in tissue.

The biological activity of a single dose of tamoxifen in the adult ovariectomized rat

“…Serum prolactin concentrations were increased in an apparently dose-related manner, being sustained for up to 4 d after tamoxifen 7.0 mg/kg. These effects upon pituitary hormone secretion are similar to those found for clomiphene (Bowman et al, 1981). LH secretion was initially increased by tamoxifen, but 16 d after administration was unexpectedly lower than in control animals.…”

“…Bowman et al (1981) showed that this activity of clomiphene was clearly dose-related, but in the present study with tamoxifen, it was not. The mechanism by which oestrogen and the oestrogen antagonists inhibit food intake and growth is not understood, one suggestion being mediation via the oestrogen receptor system of the hypothalamus.…”

“…High affinity oestrogen receptor concentrations after tamoxifen have recently been described and the receptor concentrations return to control values before control values of food intake and body weight are re-established (Bowman et al, 1982b). The lowest dose of tamoxifen used in this study does not affect the hypothalamic receptors (Bowman et al, 1982b), yet changes in food intake and body weight are comparable at both doses, suggesting that these activities are unrelated to the high affinity oestrogen receptors, a view we have reached using the oestrogen antagonist clomiphene (Bowman et al, 1981).…”

“…Tamoxifen acted as an oestrogen agonist in terms of the regulation of body weight and food intake and this was manifest after both tamoxifen alone or in combination with oestrogen; in this respect, the action is similar to the oestrogen antagonists, clomiphene and nafoxidine (Wade & Blaustein, 1978;Bowman et al, 1981). Bowman et al (1981) showed that this activity of clomiphene was clearly dose-related, but in the present study with tamoxifen, it was not.…”

Preventive effects of antioestrogen on mammary and pituitary tumorigenesis in rats

“…Thus, CB-1 54 appears to be more efficient in anti-mammary tumorigenesis than antiE. The lack of appreciable effect on the early onset of MT or the lack of complete blockade of AC may be relevant to the property of antiE that can exhibit both antagonistic and agonistic actions (Bowman et al, 1981;Katzellenbogen et al, 1979). Oestrogen produces a direct stimulatory effect and indirectly stimulates DNA synthesis of mammary epithelial cells through hypersecretion of prolactin (Nagasawa et al, 1976).…”