A study was designed to investigate the possibility that in men estradiol (E2) has a stimulatory effect on the gonadotropin response to GnRH [gonadotropin releasing hormone]. Nine castrated adult men, who presented extremely low testosterone (T) concentrations, received 5 mg/day estradiol benzoate (E2B) i.m. every 24 h for several days, starting 5 days after orchidectomy. During E2B treatment the pituitary responsiveness to GnRH (100 .mu.g given as an i.v. bolus) was tested after 24, 48, 72, 96, 120 and 144 h of E2B administration. The pituitary responsiveness to GnRH was also tested in untreated men from day 5 to day 10 following bilateral orchidectomy. In the E2B-treated subjects the increased serum estradiol concentrations induced an initial decrease and a subsequent increase of the LH response to GnRH. The responses were decreased after 24 h of treatment; thereafter, the LH responses were progressively increased and were markedly augmented after 120 h of E2b treatment. On the contrary, during treatment, the FSH response to GnRH was preferentially blunted. In the untreated castrated men the LH and FSH responses of GnRH increased progressively from day 5 to day 10 after orchidectomy, but decreased responses were never observed during this period of observation. The maximum LH concentrations, which occurred at 30-60 min following GnRH in untreated castrated men, did not occur until 120-150 min in the E2B-treated men.