Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats.

INTRODUCTION: Estetrol (E4), a naturally occurring estrogen only produced by the human fetal liver, is being evaluated in human studies for potential use in contraception and menopausal care. The present study was designed to profile E4 in the central nervous system, to assess the in vivo effects of E4 administration on allopregnanolone (AP) synthesis in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated AP synthesis. MATERIAL AND METHODS: 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 AP were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum. RESULTS: E4 did not alter AP in intact animals in any region. E4 at a dosage of 5mg/kg/day increased AP levels in different brain areas and in the serum of OVX animals. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect on the brain and serum levels of AP. CONCLUSION: E4 increases the CNS and peripheral levels of AP, behaving as a weak estrogen-agonist in OVX rats. The antagonistic effect observed with E2V co-administration further profile E4 as a natural SERM.