In nine patients with Klinefelter's syndrome, mean basal plasma levels of testosterone (302 +/- 145 ng/100 ml) and its major precursor, 17 alpha-hydroxyprogesterone (17-OHP; 86 +/- 46 ng/100 ml), were significantly lower (P less than 0.01 to less 0.05) than in eight eugonadal men (605 +/- 180 and 136 +/- 39 ng/100 ml, respectively). The ratio of 17-OHP to testosterone, however, was comparable in both groups (0.29 +/- 0.09 vs. 0.24 +/- 0.08; P less than 0.10). In the Klinefelter patients, basal plasma testosterone and 17-OHP levels were positively correlated (rs = 0.87). Administration of hCG for 3 days raised plasma testosterone and 17-OHP levels in both groups. In the Klinefelter patients, the plasma 17-OHP rise exceeded the testosterone increment, leading to a statistically significant increase (0.48 +/- 0.19) of the 17-OHP to testosterone ratio, whereas this ratio remained virtually unchanged in the control subjects (0.20 +/- 0.06). Together, these findings indicate that in the basal state testicular steroidogenesis is globally attenuated, whereas short term hCG stimulation shows that the later steps in the biosynthesis of testosterone may be rate limiting in Klinefelter's syndrome.