Dual effect of clomiphene citrate on pituitary gonadotropin secretion in postmenopausal women.

Abstract

SynopsisFifteen postmenopausal women were given 25mg, 50mg of clomiphene citrate daily by mouth for 3 consecutive days. Significant (p<0.01) decrease of serum LH (73%, 65%) and FSH (76%, 76%) resulted after administration of 25mg and 50mg clomiphene citrate respectively.The suppressive effect was sustained for at least 4 days after cessation of this drug.On the other hand decreased LH and FSH levels after administration of ethinyl estradiol increased again by simultaneous administration of clomiphene citrate. These results suggest that estrogenic effects of clomiphene citrate are observed in untreated estrogen deficient subjects but anti-estrogenic effects are evident when serum estrogen levels are restored in subjects with estrogen deficiency.Clomiphene citrate is a derivative of the synthetic estrogen TACE (chlorotrianisene) and promotes LH and FSH release by its anti-estrogenic effect (Vaitukaitis et al., 1971;Vandenberg and Yen, 1973). The anti-estrogenic effect of clomiphene has been extensively investigated and well documented (Igarashi et al., 1967;Kato et al., 1968 ;Kastin et al., 1970).On the other hand, clomiphene citrate has been found to possess weak estrogenic effects on peripheral tissue (Coppola and Perrine, 1965 ;Roy et al., 1964) and in sexual behavior in rats (Ross et al., 1973). However few systematic studies have been published concerning the estrogenic effect of clomiphene citrate of hypothalamus or pituitary gland, although Czygan and Schulz (1972) have reported inhibitory effect of the drug on LH and FSH release in postmenopausal women.Our study was so carried out as to ascertain the estrogenic and anti-estrogenic effects of this compound on hypothalamus or pituitary gland in nostmenonausal women. Materials and Methods SubjectsFifteen postmenopausal women, aged 52-66 years, without clinical evidence of disease, from whom informed consent had been obtained were given 25mg, 50mg of clomiphene citrate daily by mouth for 3 consecutive days. Three subjects received different doses of clomiphene citrate on different occasions, more than one month apart, in order to study the dose-related response.Three subjects. were given 0.1mg of ethinyl estradiol alone for 5 days, and 3 weeks later, when the decreased basal gonadotropin levels returned, the same dosage of ethinyl estradiol was given to the same subjects for 5 days with simultaneous administration of 200mg clomiphene citrate from the 3rd day. MethodsSerum LH and FSH were measured by radioimmunoassay method as described elsewhere (Hashi-

Role of Gonadal Steroids in the Serotoninergic Control of Prolactin Secretion in Men

“…It has been shown that, at pituitary and hypothalamic levels, clomiphene citrate acts either as predominant oestrogen agonist or antagonist, depending on the prevailing oestrogenic environment (Hashimoto et al, 1976;Adashi et al, 1981;Tsutsumi et al, 1983). These findings suggest that the hypothalamic serotoninergic control of PRL secretion may be regulated, in part, by gonadal steroids.…”

“…We therefore estimated the PRL response to fenfluramine, a drug which stimulates serotoninergic receptors by releasing serotonin and inhibiting its re-uptake (Fuller etal., 1981;Barbieri et al, 1983;Scarduelli etal., 1985), in normal and in castrated male subjects. The results were evaluated before and after treatment with clomiphene citrate, an oestrogen antagonist and partial agonist, whose effect depends upon the prevailing oestrogen level (Hashimoto et al, 1976;Adashi et a/., 1981;Tsutsumi et al, 1983).…”

Effects of clomiphene and raloxifene on gonadotrophin secretion in postmenopausal women: evidence of nongenomic action

“…In terms of hormonal secretion, clomiphene in oestrogen-deprived postmenopausal women demonstrates mainly oestrogenic activities suppressing basal and GnRH-induced gonadotrophin secretion, an effect that can be reversed by oestrogen pretreatment (Hashimoto et al ., 1976a;Messinis & Templeton, 1990). In terms of hormonal secretion, clomiphene in oestrogen-deprived postmenopausal women demonstrates mainly oestrogenic activities suppressing basal and GnRH-induced gonadotrophin secretion, an effect that can be reversed by oestrogen pretreatment (Hashimoto et al ., 1976a;Messinis & Templeton, 1990).…”

Oestradiol stimulates prolactin secretion in women through oestrogen receptors

“…Several pharmaceutical compounds with anti‐oestrogenic properties are used in clinical practice but there are differences in their action in the various tissues. In terms of gonadotrophin secretion, clomiphene citrate acts as an oestrogenic compound in oestrogen‐deprived postmenopausal women and as an anti‐oestrogenic when the women are pretreated with oestrogen 11,12 . Raloxifene is a new anti‐oestrogenic drug that shows actions that are different from those of clomiphene regarding the secretion of gonadotrophins with no oestrogenic activity in postmenopausal women 13 .…”

“…In terms of gonadotrophin secretion, clomiphene citrate acts as an oestrogenic compound in oestrogendeprived postmenopausal women and as an anti-oestrogenic when the women are pretreated with oestrogen. 11,12 Raloxifene is a new anti-oestrogenic drug that shows actions that are different from those of clomiphene regarding the secretion of gonadotrophins with no oestrogenic activity in postmenopausal women. 13 Data on the effects of these agents on PRL secretion are scanty and mainly based on experiments in animals.…”