Context. In aging men, circulating testosterone (T) declines which is associated with an increase in the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), albeit insufficient to maintain T at its original level. It has been speculated that a higher sensitivity of the hypothalamus and/or pituitary for the feedback effect of circulating sex hormones in older men is responsible. Objective. To compare the effect of experimentally varied plasma levels of estradiol on the LH and FSH secretion in young and old castrated male-to-female transsexuals, in almost absence of T. Design, subjects, and interventions. In 10 healthy, young (mean age 37.6 +/- 6.2 years) and 11 healthy, old (mean age 68.1 +/- 7.0) male-to-female transsexuals after gonadectomy plasma estradiol levels were experimentally varied with estradiol patches (the first week 100 mu g/day patches, the second week 50 mu g/day, the third week 25 mu g/day and the fourth week no patch was applied) and plasma levels of LH and FSH were monitored after every week. Results. Mean plasma bioavailable estradiol (E2) levels in the two groups ranged between 13.6 and 104 pmol/l. LH and FSH were inversely related to peripheral estradiol levels, were lower in the old group at all time points reaching statistical significance in the last week of the study when no patch was applied and estradiol levels were extremely low. Conclusions. The results of this study do not support the hypothesis of an age related increasing sensitivity of the hypothalamo-pituitary compartment for the negative feedback of E2, but suggest a deficient feed-forward drive in older male-to-female transsexuals.