Introduction: Estetrol (E4), a naturally occurring estrogen produced exclusively by human fetal liver, is currently being evaluated for potential use in contraception and menopausal care in humans. The present study was designed to profile E4 effects on the central nervous system, to assess the in vivo effects of E4 administration on Beta-Endorphin (β-END) release in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated β-END synthesis.
Experimental: Intact female adult rats received different doses of E4 and ovariectomized (OVX) rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of β-END were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, neurointermediate lobe, anterior pituitary and plasma.
Results: E4 at the dose of 1mg/kg/day did not alter β-END content in most brain areas, as well as, plasma levels of intact animals E4 administered at a dose of 5mg/kg/day decreased β-END content in the hippocampus, hypothalamus, and in the neurointermediate lobe, as well as, plasma levels, compared to intact animals receiving vehicle. E4 increased β-END values in the frontal cortex, but not in the plasma, following the administration of 1mg/kg/day in OVX rats, whereas treatment with 5mg/kg/day in OVX rats induced a significant increase in β-END levels in most brain areas and in the plasma. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect in selected brain structures at the dose of 5mg/kg/day and in plasma levels of β-END at the dose of 1mg/kg/day and 5mg/kg/day.
Conclusion: In OVX rats, E4 increases CNS and peripheral levels of β-END, behaving as a weak estrogen-agonist. The antagonistic effect observed after combined estradiol and E4 administration further profiles E4 as a natural SERM.
Keywords: Brain; Endorphin; Estetrol; Plasma; SERMs.
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