Differences in the rates of affective disorders between women and men may relate to gender differences in gonadal steroid levels such as estrogen that have effects on brain monoamines important to mood regulation. Changes in estrogen secretion patterns during the perimenopause and menopause may be relevant to the increased risk for affective symptoms at that time. This study examined whether 17beta-estradiol (E2) administration can modify the mood effects of experimental psychosocial stress following acute monoamine depletion in postmenopausal women. Subjects consisted of 15 normal postmenopausal women (PMW) (ages 67.1+/-11.2 years) blindly placed on either oral placebo or E2 (1 mg/day for 1 month, then 2 mg/day for 2 months). At the end of the 3-month treatment phase, subjects participated in three blinded depletion challenges in which they ingested each of three amino-acid mixtures: deficient in tryptophan, deficient in phenylalanine/tyrosine, or nutritionally balanced. After 5 h, subjects performed the Trier Social Stress Test (TSST), followed by mood and anxiety ratings. E2-treated subjects exhibited a significant increase in negative mood and anxiety after the TSST compared to placebo-treated women. These effects were independent of monoamine depletion and were not manifest before the TSST or at baseline. Exogenous estrogen administration in PMW may alter or modulate emotional reactivity to stressful events and may alter the sensitivity of emotional regulation. This modulation appears to be independent of alterations in monoaminergic neurotransmission. The dose of estrogen used after menopause may be important in determining the effects of gonadal steroids on emotional regulation.