Pluchino N, Drakopoulos P, Casarosa E, Freschi L, Petignat P, Yaron M, Genazzani A R
Division of Obstetrics and Gynecology, University Hospital of Geneva, Switzerland.
Division of Obstetrics and Gynecology, University Hospital of Geneva, Switzerland.
Steroids. 2015 Mar;95:104-10. doi: 10.1016/j.steroids.2015.01.003. Epub 2015 Jan 13.
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.
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.
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.
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.
雌三醇（E4）是一种仅由人类胎儿肝脏产生的天然雌激素，目前正在评估其在人类避孕和更年期护理中的潜在用途。本研究旨在剖析E4对中枢神经系统的影响，评估E4给药对特定脑结构中β-内啡肽（β-END）释放的体内效应，并评估E4对雌二醇介导的β-END合成是否具有协同或拮抗作用。
成年未切除卵巢的雌性大鼠接受不同剂量的E4，切除卵巢的（OVX）大鼠接受不同剂量的E4或雌二醇戊酸酯（E2V）或两种药物的组合。在额叶和顶叶皮质、海马体、下丘脑、神经中间叶、垂体前叶和血浆中评估β-END的浓度。
与接受赋形剂的未切除卵巢的动物相比，以1mg/kg/天的剂量给药E4不会改变大多数脑区以及未切除卵巢的动物血浆中的β-END含量。以5mg/kg/天的剂量给药E4会降低海马体、下丘脑和神经中间叶中的β-END含量以及血浆水平。在切除卵巢的大鼠中，以1mg/kg/天的剂量给药E4后，额叶皮质中的β-END值升高，但血浆中未升高，而在切除卵巢的大鼠中以5mg/kg/天的剂量治疗会导致大多数脑区和血浆中的β-END水平显著升高。然而，在存在雌二醇的情况下，E4在5mg/kg/天的剂量下在选定的脑结构中以及在1mg/kg/天和5mg/kg/天的剂量下在β-END的血浆水平中表现出雌激素拮抗作用。
在切除卵巢的大鼠中，E4会增加中枢神经系统和外周β-END水平，表现为一种弱雌激素激动剂。雌二醇和E4联合给药后观察到的拮抗作用进一步表明E4是一种天然的选择性雌激素受体调节剂（SERM）。
