In women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) increased negative mood symptoms are related to progesterone and its metabolite allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. The negative mood symptoms similar as in PMS reoccur during progesterone/allopregnanolone addition in sequential hormone therapy (HT). The symptoms are not mediated by the classical hormonal progesterone receptor as the progesterone receptor antagonist mefipristone does not inhibit the symptoms. Therefore, one hypothesis is that the symptoms are provoked by progesterone metabolites active on the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. A positive modulator of the GABA-A receptor is the progesterone metabolites allopregnanolone. In certain individuals' positive GABA-A receptor modulators, including allopregnanolone, have biphasic effects. In low physiological concentrations, as during the luteal phase, they paradoxically give strong adverse, anxiogenic effects in 3-8%, and in up to 25% moderates symptoms in premenopausal women. In higher concentrations the compounds show calming properties. Treatments with a GABA-A modulating steroid antagonist (10mg every second day) significantly decreases negative mood symptoms in patients with PMDD, suggesting that this can be a new treatment of PMS/PMDD.