Sensitivity to a neurosteroid is increased during addition of progestagen to postmenopausal hormone replacement therapy

The aim of this study was to compare the pharmacodynamic response to a neur oactive steroid, pregnanolone, before and during different hormonal setting s of postmenopausal hormone replacement therapy (HRT). Twenty-seven postmen opausal women with climacteric symptoms were administered HRT in a randomiz ed, double-blinded, placebo-controlled crossover study. The women received 2 mg estradiol (E-2) continuously during four 28-day cycles and 10 mg medro xyprogesterone acetate (MPA), 1 mg norethisterone acetate (NETA) or placebo sequentially for the last 14 days in each cycle, The pharmacodynamic respo nse to pregnanolone was assessed before treatment and during the last week of each treatment, by comparing the effects of intravenous pregnanolone (3 alpha -hydroxy-5 beta -pregnan-20-one) on saccadic eye velocity (SEV), sacc ade deceleration, saccade latency and self-rated sedation. Throughout the s tudy daily symptom rating scales were kept. During the progesta gen phase o f the treatment cycles, negative mood symptoms and physical symptoms were i ncreased, whereas positive mood symptoms were decreased. Compared to pretre treatment conditions, E-2 alone did not change the responsiveness to pregna nolone. During progestagen addition to E-2, the responsiveness to pregnanol one was increased. The sedation response increased compared to pretreatment conditions during both E-2 + MPA and E-2 + NETA treatment. Compared to E-2 treatment alone, addition of MPA increased the postpregnanolone effect on saccade deceleration, whereas the SEV response to pregnanolone was increase d during E-2 + NETA treatment. It is concluded that pregnanolone sensitivit y increases together with deterioration in mood symptoms during addition of progestagen to HRT. Copyright (C) 2001 S. Karger AG, Basel.