To study the opioid control on LH and FSH secretion in Klinefelter subjects (KS), the response of gonadotropin to an opioid antagonist, naloxone, was examined in 8 KS (age range 25-35 yrs) and in 8 age matched normal men. In 6 KS with low testosterone plasma levels, naloxone infusion were also performed after treatment with testosterone enanthate, 200 mg i.m. every 3 weeks for 4 months. FSH did not show any important variation in KS and in normal men during naloxone infusion. In KS the percentage of naloxone induced LH increase was significantly lower than in controls and there was no correlation between testosterone plasma levels and LH increase after naloxone infusion. LH increases after naloxone infusion were not significantly different before and after testosterone treatment. The increases of naloxone induced LH plasma levels, before and after testosterone treatment, correlated well between themselves (r = 0.93-p less than 0.01). Plasma levels decreased in all patients after testosterone treatment, but only in two was there a return to normal range. There is a clearly positive linear correlation between the percentage of LH decrease after testosterone treatment and LH increase after naloxone infusion (r = 0.81; p less than 0.01). After testosterone therapy FSH plasma levels fall by 63 +/- 15% in all patients and did not show any important variation after naloxone infusion. In conclusion, our data are in agreement with the hypothesis that in Klinefelter's syndrome an alteration of opioid control on gonadotropin secretion may exist. This alteration does not appear to be due to androgen deficiency, but rather it may be caused by genetic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)