title: Effect of long-term treatment with the antiestrogen EM-652.HCl on pituitary estrogen receptor alpha and prolactin mRNA expression in intact, ovariectomized and gonadotropin-releasing hormone-treated female rats.
abstract: Estrogen receptor alpha (ERalpha) is the predominant estrogen receptor subtype in the anterior pituitary gland. In order to assess the influence of the pure antiestrogen EM-652.HCl on ERalpha gene transcription, we have studied the effect of long-term administration of the antiestrogen in ovariectomized rats as well as in intact female rats treated or not with the GnRH-agonist D-trp(6), des-Gly-NH2(10) GnRH ethylamide (GnRH-A), a treatment which induces pharmacological castration. To evaluate the degree of pituitary responsiveness to changes in estrogen exposure, prolactin (PRL) mRNA levels were also measured. ERalpha and PRL mRNA levels were evaluated by quantitative in situ hybridization. It was found that, 49 weeks after ovariectomy (OVX), pituitary ERalpha mRNA levels were decreased by 55%. Long-term administration (49 weeks) of EM-652.HCl to OVX animals resulted in a further 41% decrease in ERalpha mRNA. On the other hand, ovariectomy induced an 82% decrease in PRL mRNA levels while the administration of EM-652.HCl to OVX animals did not further decrease PRL mRNA. The administration of EM.652.HCl or GnRH-A alone to intact rats during 52 weeks did not significantly modify pituitary ERalpha mRNA levels. Concomitant administration of both GnRH-A and EM-652.HCl induced 41 and 47% decreases in ERalpha mRNA levels, when compared to the levels measured in vehicle-treated and GnRH-treated animals respectively. Combined administration of EM.652.HCl and GnRH-A induced 56 and 65% decreases in PRL mRNA, respectively. When EM-652.HCl was administered concomitantly with GnRH-A, the inhibitory effect on PRL mRNA levels was more marked than that observed in GnRH-A-treated animals. The present data demonstrate that when circulating estrogens are absent or maintained at very low levels by GnRH administration, EM-652.HCl can still depress ERalpha gene transcription. It is suggested that estrogens can positively regulate pituitary ERalpha gene transcription and that the antiestrogen EM-652.HCl can downregulate by itself pituitary ERalpha gene transcription.
authors.affiliation: Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), and Laval University, Québec, Canada. georges.pelletier@crchul.ulaval.ca
authors.forename: G
authors.initials: G
authors.lastname: Pelletier
authors.forename: M
authors.initials: M
authors.lastname: El-Alfy
authors.forename: C
authors.initials: C
authors.lastname: Labrie
authors.forename: C
authors.initials: C
authors.lastname: Martel
authors.forename: F
authors.initials: F
authors.lastname: Labrie
mesh_terms: D000818:Animals; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D010052:Ovariectomy; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism; D011388:Prolactin / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics*; D012016:Reference Values; D013997:Time Factors
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D010880:Piperidines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D007987:Gonadotropin-Releasing Hormone; C012121:ritetronium; D011388:Prolactin