Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone

Objective: To compare severity of negative mood, and physical symptoms between women with different progesterone, allopregnanolone, and pregnanolone plasma concentrations during sequential Hormone Replacement Therapy (HRT) with vaginal progesterone suppositories. Design: A randomized, placebo-controlled, double-blind, crossover study. Method: Postmenopausal women (n = 36) with climacteric symptoms were treated with 2 mg estradiol daily during three 28-day cycles. Vaginal progesterone suppositories with 400, 800 mg/day or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale W. ere kept. Blood samples for progesterone, allopregnanolone, and pregnanolone radioimmunoassays were collected during each treatment cycle. Results: Women were divided into three groups (tow, medium, and high) based on plasma allopregnanotone concentration during progesterone treatment. The concentration of allopregnanolone in the medium group corresponds to the concentration seen during the mid luteal phase of the menstrual cycle. Within women with medium allopregnanolone concentration significantly more negative mood and physical symptoms were rated during progesterone treatment compared to treatment with unopposed estrogen or placebo. Between women significantly more negative mood symptoms were seen during progesterone treatment cycles with medium allopregnanotone concentration compared to cycles with low concentration. Plasma progesterone, allopregnanotone, and pregnanolone concentrations increased with increasing progesterone dose. Progesterone and allopregnanotone plasma concentrations increased 2 h after vaginal administration of progesterone at 400 and 800 mg/day. Conclusion: Vaginal progesterone in sequential HRT causes negative mood, most likely mediated via allopregnanolone. (C) 2004 Elsevier Ltd. All rights reserved.