We tested the hypothesis that changes in endogenous neuroactive steroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors may be related to the menopause-associated mood alterations. The study sample consisted of twenty five drug-free menopausal women, 1-3 years since the onset of menopause, homogeneous for age and body mass index (BMI) and without personal history of psychiatric, metabolic or endocrine disorders. Depression and anxiety-related symptoms were assessed with the Zung Self-administered Depression Scale (ZSDS) and the Cornell's Dysthymia Rating Scale (CDRS). The cut-off value predicted by the ZSDS index defined two groups of women (asymptomatic [35.5+/-4.6, n=12] and symptomatic [60.8+/-7.9, n=13]), that were also significantly different according to the CDRS scores (10.6+/-3.4 and 31.5+/-12, respectively, P<0.05). Upon evaluation of the scores relative to the anxiety factor of the CDRS (items 11-15) the symptomatic, but not the asymptomatic, group showed a moderate level of anxiety. The plasma concentrations of several neuroactive steroids were measured, after extraction and HPLC purification, by radioimmunoassay with specific antisera. Only dehydroepiandrosterone and its metabolite 5alpha-androstane-3alpha,17betadiol (3alpha-ADIOL), a positive allosteric modulator of GABA(A) receptors, were significantly (P<0.05 and P<0.005) higher (+110% and +64%, respectively) in the asymptomatic group. A highly significant and negative correlation (r=-0.672, P=0.003) was found between the plasma 3alpha-ADIOL concentrations and the scores of the anxiety factor of the CDRS. These data suggest that endogenous 3alpha-ADIOL modulates the central GABAergic tone and that higher 3alpha-ADIOL concentrations could have a role in preventing the expression of anxiety in the asymptomatic women.