Evidence that neurosteroids have anxiolytic effects in animal models of anxiety has suggested that alterations of neurosteroid secretion might be implicated in the pathogenetic mechanisms of anxiety disorders in humans. In 25 female patients with panic disorder (PD) and 11 healthy female controls, we measured plasma concentrations of progesterone (PROG), pregnenolone (PREG), allopregnanolone (3alpha,5alpha-tetrahydroprogesterone=3alpha,5alpha-THPROG), dehydroepiandrosterone (DHEA) and tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) during a drug-free month and during the following month of paroxetine therapy. The neurosteroids were measured during the early follicular phase, the mid-luteal phase and the premenstrual phase of both months (days 7, 22 and 27 from the beginning of the cycle). Significantly higher levels in patients than controls were found in PROG during the mid-luteal phase of both months, PREG in the premenstrual phase in the drug-free month, 3alpha,5alpha-THPROG during the follicular phase of the drug-free month and during the premenstrual phase of the therapy month, and 3alpha,5alpha-THDOC during the premenstrual phases of both months. DHEA levels did not differ in patients and controls. These results suggest that neurosteroids in PD are hypersecreted, possibly as an attempt to counteract the anxiogenic underlying hyperactivity of the hypothalamo-pituitary-adrenal axis and to improve a reduced GABA(A) receptor sensitivity.