A paradoxical inhibitory effect of oestradiol-17β on GnRH self-priming in pituitaries from tamoxifen-treated rats

Abstract

Two-week ovariectomized (OVX) rats were injected over three days with 25 µg oestradiol benzoate (EB), 3 mg tamoxifen (TX) and 0·2 ml oil and their pituitaries were harvested for incubation experiments. Pituitaries from EBand TX-treated OVX rats exhibited GnRH self-priming when incubated with their corresponding ligand. However, incubation of pituitaries with different ligands yielded divergent results: when pituitaries from EBtreated rats were incubated with 10 7 M TX they displayed GnRH self-priming, whereas incubation of pituitaries from TX-treated rats with 10 8 M oestradiol-17 (E 2 ) blocked GnRH self-priming. Further studies to analyse the latter finding revealed that: (a) E 2 inhibited TX-induced GnRH self-priming in a dose-dependent manner while 10 8 M oestradiol-17 did not; (b) coincubation of E 2 with the pure anti-oestrogen ICI 182,780, but not with the selective oestrogen receptor modulator TX, reversed the E 2 inhibitory effect; (c) the oestrogen receptor (ER)-selective agonist propylpyrazole triol, but not the ER selective agonist diarylpropionitrile, mimicked the inhibitory effect of E 2 ; (d) the analogue membrane-impermeable conjugated E 2 -BSA also inhibited TX-induced GnRH self-priming; and (e) a 15-min exposure of the pituitaries to E 2 was sufficient to inhibit the GnRH self-priming elicited by TX. Although other explanations may exist, altogether these results suggested that E 2 , via an ER different from classical ER, inhibits the GnRH self-priming elicited by TX.

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

“…This ovary-mediated effect of hFSH could be pointing to an inefficient response of gonadotroph PR to physiological phosphorylation/activation induced by P 4 and PKA or PKC (Denner et al 1990, Zhang et al 1994, which are ligand-dependent and -independent activators of PR respectively. It has been found that E 2 inhibits PR action and LHRH self-priming by activating membrane ERa of the gonadotroph both in vitro (Sánchez-Criado et al 2005) and in vivo (Garrido-Gracia et al 2007). The inhibitory action of activated membrane ERa on LH secretion is reverted by inhibition of intracellular phosphatases and mimicked by the stimulation of protein phosphatases .…”

The integrated action of oestrogen receptor isoforms and sites with progesterone receptor in the gonadotrope modulates LH secretion: evidence from tamoxifen-treated ovariectomized rats

“…Moreover, addition of the pure type II anti-oestrogen ICI182 780 (Smith & O'Malley 2004) to the medium blocks the rapid inhibitory action of E 2 on TX-elicited LHRH self-priming, whereas TX itself does not (Sánchez-Criado et al 2005b). One emerging explanation of these in vitro data is that TX selectively binds nuclear ERa but not ERb (Tzuckerman et al 1994, Bellido et al 2003, Sánchez-Criado et al 2004, 2005a) and exhibits extremely low affinity for membrane ERa in rat gonadotropes (Sánchez-Criado et al 2005b). In addition, these data suggest that E 2 inhibition of TX-elicited LHRH self-priming is due to activation of the plasma membrane ERa (Sánchez-Criado et al 2005b, 2006b).…”

“…Evidence derived from in vitro work indicates that the agonist actions of TX in the rat gonadotrope are exerted at the nuclear ERa level exclusively. Therefore, incubated pituitaries from OVX rats injected over 3 days with pharmacological doses of TX exhibit LHRH self-priming (Sánchez-Criado et al 2005b) and this agonistic effect of TX is inhibited when E 2 or the membrane-impermeable analogue conjugated E 2 -BSA is added to the incubation medium. Moreover, addition of the pure type II anti-oestrogen ICI182 780 (Smith & O'Malley 2004) to the medium blocks the rapid inhibitory action of E 2 on TX-elicited LHRH self-priming, whereas TX itself does not (Sánchez-Criado et al 2005b).…”

“…Therefore, incubated pituitaries from OVX rats injected over 3 days with pharmacological doses of TX exhibit LHRH self-priming (Sánchez-Criado et al 2005b) and this agonistic effect of TX is inhibited when E 2 or the membrane-impermeable analogue conjugated E 2 -BSA is added to the incubation medium. Moreover, addition of the pure type II anti-oestrogen ICI182 780 (Smith & O'Malley 2004) to the medium blocks the rapid inhibitory action of E 2 on TX-elicited LHRH self-priming, whereas TX itself does not (Sánchez-Criado et al 2005b). One emerging explanation of these in vitro data is that TX selectively binds nuclear ERa but not ERb (Tzuckerman et al 1994, Bellido et al 2003, Sánchez-Criado et al 2004, 2005a) and exhibits extremely low affinity for membrane ERa in rat gonadotropes (Sánchez-Criado et al 2005b).…”

“…The present study was designed to ascertain whether the in vitro inhibitory effects of both nuclear ERb-initiated signalling (Sánchez-Criado et al 2004) and membrane ERainitiated signalling (Sánchez-Criado et al 2005b) upon the LH secretory actions of the nuclear ERa-initiated signalling were also operative in the whole animal. To this purpose, three groups of in vivo experiments were conducted: the first, to verify the effects of TX on LH secretion, pituitary PR expression and LHRH self-priming in 2-week OVX rats; the second, to evaluate the role of the different ER isoforms and sites in LH release in gonadotropes with TX-activated nuclear ERa using the cognate ligand E 2 and the selective ERa and ERb agonists PPT and DPN respectively and the third to verify that TX acts through ERa by studying the effects of the selective ERa antagonist MPP.…”