Disparate effect of clomiphene and tamoxifen on pituitary gonadotropin release in vitro

Abstract

The direct effects of clomiphene citrate (Clomid), tamoxifen, and estradiol (E2) on the gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in cultured anterior pituitary cells obtained from adult ovariectomized rats. Treatment of pituitary cells with Clomid or enclomid (10(-8) M) in vitro for 2 days resulted in a marked sensitization of the gonadotroph to GnRH as reflected by a 6.5-fold decrease in the ED50 of GnRH in terms of LH release from 2.2 x 10(-9) M in untreated cells to 3.6 x 10(-10) M. Treatment with E2 or Clomid also increased the sensitivity of the gonadotroph to GnRH in terms of FSH release by 4.3- and 3.3-fold respectively. Tamoxifen, a related antiestrogen, comparable to Clomid in terms of its ability to compete with E2 for pituitary estrogen receptors, was without effect on the GnRH-stimulated LH release at a concentration of 10(-7) M. Furthermore, tamoxifen, unlike Clomid, caused an apparent but not statistically significant inhibition of the sensitizing effect of E2 on the GnRH-stimulated release of LH. Our findings suggest that Clomid and its Enclomid isomer, unlike tamoxifen, exert a direct estrogenic rather than an antiestrogenic effect on cultured pituitary cells by enhancing the GnRH-stimulated release of gonadotropin.

The pathophysiology of polycystic ovary syndrome

“…An alternative possibility is that the reduced secretion of LH with these therapies could be secondary to high progesterone levels following ovulation. Finally, insulin receptors have been identified in human pituitary tissue (Unger et al ., 1991) and insulin found to stimulate gonadotropin release in vitro , at least in rats (Adashi et al ., 1981). Nestler et al .…”

Therapeutic Effect of Silybum marianum Plant Extract on Tamoxifen-Induced Fatty Liver in Rats

“…It is also used for infertility treatment due to its stimulatory effect on the secretion of pituitary gonadotropin hormones (2,3). Despite the beneficial effects of TMX, the use of this drug has several side effects in patients with breast cancer (4).…”

Clomiphene citrate induces pituitary GnRH receptors in ovariectomized rats: its possible role in induction of ovulation

“…Clomiphene has been shown to act as both oestrogen agonist and anta¬ gonist, depending on target tissues, duration of treatment and availability of oestrogen in the system (Clark et al 1974). It has also been re¬ ported that clomiphene, unlike tamoxifen, sensi¬ tizes gonadotrophs to GnRH, resulting in an en¬ hancement of release of LH from pituitary cells in culture (Adashi et al 1981 ;Huang & Miller 1983). On the other hand, however, previous studies (Tsutsumi et al 1983) have demonstrated that clomiphene administration results in the reduc¬ tion of pituitary weight and the suppression of progesterone receptor synthesis in chronically oestrogenized rats.…”

“…hypothalamic-pituitary system during the follicu¬ lar phase and consequently increases serum levels of gonadotrophin. Studies with cultured pituitary cells, however, have suggested that clomiphene exerts an oestrogenic rather than anti-oestrogenic effect on the pituitary cells by enhancing GnRH stimulated release of gonadotrophin (Adashi et al 1981;Huang & Miller 1983). Clomiphene, unlike oestradiol-17ß (E2), has also been shown to act as a long-acting agent in the pituitary gland (Adashi et al 1980;Tsutsumi et al 1983).…”