This study has evaluated the effect of the estrogen antagonist clomiphene citrate on the exaggerated PRL response to TRH and the dopaminergic antagonist metoclopram-ide (MET) in 16 patients with primary testicular failure and elevated basal and peak gonadotropin responses to LRH. Subjects were challenged with LRH (100 µg), TRH (200 µg), and MET (10 mg), given iv at 30-min intervals in the basal state and after clomiphene citrate, administered as a daily dose of 100 mg for 4 weeks (10 subjects), 200 mg for 4 weeks (3 subjects), and 100 mg for 8 weeks (3 subjects). The patients were subdivided into 2 groups on the basis of the PRL response to TRH and MET, which was exaggerated in 12 subjects (group I) and similar to the controls in 4 subjects (group II). Mean basal LH, FSH, and LH (but not FSH) responses to LRH were increased post clomiphene treatment in both groups. Testosterone levels were normal in both groups, but 17β-estradiol (E2) levels were in)creased in group I. After clomiphene administration, both testosterone and E2 increased in group I subjects. Basal PRL levels were normal in both groups, and there was no change after clomiphene treatment. However, the exaggerated PRL responses to both TRH and MET in group I subjects were decreased after clomiphene administration. Nevertheless, levels were still greater than those in the controls. In contrast, in group II subjects, the PRL response to TRH or MET was not altered by clomiphene. The reduction in the exaggerated PRL response to TRH and MET consequent to clomiphene administration in group I subjects implies that this phenomenon is likely to be estrogen induced. This is supported by the high E2 levels in this group of patients.