Differential effects of centrally-administered oestrogen antagonist ICI-182,780 on oestrogen-sensitive functions in the hypothalamus.
Oestrogen actions within the hypothalamus are essential for a range of reproductive functions. In this study, we sought to develop a method for suppressing central oestrogen action without affecting peripheral oestrogenic effects. We administered the oestrogen receptor antagonist ICI-182,780 (ICI) via crystalline implants into the left lateral ventricle or the arcuate nucleus and measured the effectiveness of this drug on three endpoints known to be regulated by oestrogen: gonadotrophin-releasing hormone (GnRH) pulse frequency, progesterone receptor expression and the generation of a sustained prolactin surge during late pregnancy. To confirm that central ICI administration had no effect on peripheral actions of oestrogen, we monitored changes in uterine weight. Intracerebroventricular ICI treatment reversed the inhibitory effects of oestrogen on GnRH pulse frequency, as measured by plasma luteinising hormone pulse frequency. No effect on the oestrogenic induction of progesterone receptors within the arcuate nucleus or ventromedial hypothalamus was observed; however, a small yet significant reduction in progesterone receptor expression within dopaminergic neurones in the arcuate nucleus was observed. Intracerebroventricular or direct crystalline ICI administration to the arcuate nucleus did not change the serum prolactin level during late pregnancy. Central administration of ICI did not affect uterine weight, and thus did not have a peripheral effect. These data suggest that central administration of ICI can overcome some actions of oestrogen in the brain, such as GnRH pulse frequency, but does not affect other oestrogen mediated actions, including the induction of progesterone receptors or the antepartum prolactin surge. Thus, it appears that there is a differential sensitivity to the inhibition of central oestrogen actions by ICI.
Steyn
F J
FJ
Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand.
Anderson
G M
GM
Grattan
D R
DR
D000818:Animals; D004333:Drug Administration Routes; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007986:Luteinizing Hormone / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D011673:Pulsatile Flow / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000378:metabolism
D004965:Estrogen Antagonists; D004967:Estrogens; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol; D011388:Prolactin; D007986:Luteinizing Hormone