Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder

Background: This study was designed to examine basal anti stress-induced le vels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examin ed. An additional goal was to investigate the relationship between premenst rual symptom severity and luteal phase allopregnanolone levels. Methods: Twenty-four women meeting prospective criterion for PMDD were comp ared with 12 controls during both the follicular and luteal phases of confi rmed ovulatory cycles, counterbalancing phase at first testing. Plasma allo pregnanolone and cortisol were sampled after an extended baseline period an d again 17 min following the onset of mental stress. Owing to low follicula r phase allopregnanolone levels, only luteal phase allopregnanolone and cor tisol were analyzed. Results: During the luteal phase, PMDD women had significantly greater allo pregnanolone levels, coupled with significantly lower cortisol levels, duri ng both baseline and mental stress. Moreover, significantly more controls ( 83%) showed the expected stress-induced increases in allopregnanolone compa red with PMDD women (42%). Premenstrual dysphoric disorder women also exhib ited a significantly greater alllopregnanolone/progesterone ratio than cont rol subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women wit h greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less sympt omatic PMDD women. No relationship between symptom severity and allopregnan olone was observed in controls. Conclusions: These results suggest dysregulation of allopregnanolone mechan isms in PMDD and that continued investigations into a potential pathophysio logic role of allopregnanolone in PMDD are warranted. (C) 2001 Society of B iological Psychiatry.