Effects of estradiol and raloxifene analog on brain, adrenal and serum allopregnanolone content in fertile and ovariectomized female rats

Allopregnanolone is a neuroactive steroid synthesized in rat gonads, adrena l cortex, and central nervous system. It has been suggested that sex steroi d hormones might influence allopregnanolone concentrations but no clear dat a have ever been reported. The aim of the present study was to investigate the effects of administration of 17 beta-estradiol (17 beta-E2), the raloxi fene analog LY-117018 or their combination on allopregnanolone levels in fe rtile and ovariectomized (OVX) rats. Thirteen groups of 12 Wistar female ra ts each received either 17 beta-E2 (0.1 or 1 mu g/day) or LY-117018 (25, 25 0, and 1,250 mu g/day), or 17 beta-E2 1 mu g/day plus LY-117018: 25, 250, a nd 1,250 mu g/day for 14 days. The rats were then sacrificed and allopregna nolone content was assessed in the hypothalamus, hippocampus, pituitary, ad renals, and serum. Ovariectomy determined a significant decrease in allopre gnanolone content in the hypothalamus, hippocampus, pituitary, and serum, w hile increasing it in the adrenals (p < 0.01). In OVX rats, the administrat ion of either 17 beta-E2 or LY-117018 restored ovariectomy-induced allopreg nanolone changes. The administration of LY-117018 in addition to 17 beta-E2 to OVX animals suppressed the increase in allopregnanolone levels determin ed by 17 beta-E2 in the hippocampus, hypothalamus, and pituitary, but not i n the adrenals and serum. In fertile rats, the administration of LY-117018 reproduced the effects of ovariectomy. This study shows that the raloxifene analog LY-117018 has an estrogen-like action on the central nervous system of OVX rats when administered alone, while it acts as an antiestrogen in t he presence of 17 beta-E2, both in OVX animals treated with 17 beta-E2 and in fertile rats. A different effect was observed in the adrenal glands. The mechanism of action of this compound has still to be clarified. Copyright (C) 2000 S. Karger AG. Basel.