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 2mg 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 were kept. Blood samples for progesterone, allopregnanolone, and pregnanolone radioimmunoassays were collected during each treatment cycle. RESULTS Women were divided into three groups (low, medium, and high) based on plasma allopregnanolone 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 allopregnanolone concentration compared to cycles with low concentration. Plasma progesterone, allopregnanolone, and pregnanolone concentrations increased with increasing progesterone dose. Progesterone and allopregnanolone plasma concentrations increased 2h 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.