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

Abstract

The specific role of each oestrogen receptor (ER) isoform (a and b) and site (nucleus and plasma membrane) in LH release was determined in ovariectomized (OVX) rats injected over 6 days (days 15-20 after OVX) with a saturating dose (3 mg/day) of tamoxifen (TX), a selective ER modulator with nuclear ERa agonist actions in the absence of oestrogen. This pharmacological effect of TX was demonstrated by the fact that it was blocked by the selective ERa antagonist methyl-piperidino-pyrazole. Over the past 3 days of the 6-day TX treatment, rats received either 25 mg/day oestradiol benzoate (EB), 1 . 5 mg/day selective ERa agonist propylpyrazole triol (PPT) and the selective ERb agonist diarylpropionitrile (DPN), or a single 3 mg injection of the antiprogestin onapristone (ZK299) administered on day 20. Blood samples were taken to determine basal and progesterone receptor (PR)-dependent LH-releasing hormone (LHRH)-stimulated LH secretion and to evaluate LHRH self-priming, the property of LHRH that increases gonadotrope responsiveness to itself. Blood LH concentration was determined by RIA and gonadotrope PR expression by immunohistochemistry. Results showed that i) EB and DPN potentiated the negative feedback of TX on basal LH release; ii) DPN reduced TX-induced PR expression; iii) EB and PPT blocked TX-elicited LHRH self-priming and iv) ZK299 reduced LHRH-stimulated LH secretion and blocked LHRH self-priming. These observations suggest that oestrogen action on LH secretion in the rat is exerted at the classic ERa pool and that this action might be modulated by both ERb and membrane ERa through their effects on PR expression and action respectively.

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 is because no effects of hFSH on PR-A/PR-B mRNA ratio or total immunoreactive PR protein were noted. In addition, hFSH treatment did not affect, either in vivo or in vitro, basal LH secretion, a finding also in agreement with the PR-independent character of the negative E 2 feedback on LH secretion (Chappell et al 1999, Garrido-Gracia et al 2007. In full agreement with others (Manni et al 1981), a positive translational effect of the E 2 background on PR protein was evidenced.…”

“…All these facts, and the present in vitro observations of the inhibitory effect of RU486 on LHRH self-priming, demonstrated that the presence of PR and its activation are absolute requirements for the transmission of E 2 -induced signals leading to the LH surge. Treatment with FSH reduced only the magnitude of the LH surge with no effect on basal LH secretion (Geiger et al 1980, present experiments), and it would appear that FSH may well decrease the preovulatory LH release by affecting PR expression and/or action (Garrido-Gracia et al 2007).…”

“…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 .…”

Ovarian stimulation with FSH reduces phosphorylation of gonadotrope progesterone receptor and LH secretion in the rat

“…Former studies from our group had shown that membrane oestrogen receptor-initiated intracellular signalling enhances gonadotrope protein phosphatase activity and results in the inhibition of GNRH1 selfpriming (Sánchez-Criado et al 2006, Garrido-Gracia et al 2007. The aim of the present study was to analyse PR phosphorylation status in the gonadotrope of rats with impaired LH secretion induced by GnSI/AF.…”

Estrogen receptor (ESR) 2 partially offsets the absence of ESR1 in gonadotropes of pituitary-specific Esr1 knockout female mice

“…The actions of ESR1 are much better known (Parker 1995) than those of ESR2, which remain elusive (Pettersson & Gustafsson 2001, Imamov et al 2005, Koehler et al 2005, Sugiyama et al 2010. The role played by each ESR isoform in the gonadotrope is currently being studied, in vivo and in vitro, in OVX rats injected with the selective ESR1 and 2 agonists, propylpyrazole triol (PPT) and diarylpropionitrile (DPN), respectively (Sá nchez- Criado et al 2004, Garrido-Gracia et al 2007, and in global or ESR isoform-specific knockout (KO) mice (Dupont et al 2000, Hewitt & Korach 2003, Gieske et al 2008, Singh et al 2009, Kim et al 2011). …”