Since sex hormone-binding globulin (SHBG) levels are often elevated in sera of patients with testicular insufficiency, it is important to determine whether SHBG declines into the normal range and the extent of change in free testosterone (free T) after androgen administration. Five normal men and five patients with Klinefelter's syndrome were studied before and after the administration of testosterone enanthate (200 mg, im every 2 weeks). An additional five normal men and five patients with hypogonadotropic hypogonadism (HH) were treated with hCG (2000 U, three times a week). Three months after the administration of T or hCG, serum total and free T increased in both normal men and patients. Free T increased significantly in the Klinefelter's and HH patients from 94 +/- 20 and 14 +/- 5 pg/ml, respectively, to 271 +/- 50 and 276 +/- 41 pg/ml (P less than 0.01; P less than 0.001). The increase in the normal men treated with T or hCG was also significant (from 211 +/- 52 and 220 +/- 37 pg/ml to 390 +/- 83 and 330 +/- 90 pg/ml). SHBG fell in both the T-treated normal men (from 6.5 +/- 1.2 ng dihydrotestosterone bound/ml to 4.3 +/- 0.4; P less than 0.02) and the T-treated Klinefelter's patients (from 16.4 +/- 2 to 4.3 +/- 0.5; P less than 0.01). However, it was unchanged in the hCG-treated HH patients and rose in the hCG-treated normal men (from 6.6 +/- 0.7 to 8.6 +/- 1.0; P less than 0.05). This study demonstrates that treatment of hypogonadal men with T and hCG in the doses used increased free T levels above the basal levels for normal men. However, the effects of the increase in free T, as determined by a change in SHBG, were different depending upon the type of treatment.