MONITORING OF GROWTH-HORMONE REPLACEMENT THERAPY IN ADULTS, BASED ON MEASUREMENT OF SERUM MARKERS

The optimal dose for GH replacement therapy in GH-deficient (GHD) adul ts is not known, nor is there a consensus as to which method is the mo st appropriate for the monitoring of treatment. To establish a general guideline for GH replacement therapy in adults, we evaluated the rela tionship between the administered GH dose and the achieved serum level s of three GH-dependent serum markers. Serum levels of insulin-like gr owth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-l abile subunit (ALS) were measured in 46 GKD men participating in a 1-y r, double blind, and placebo-controlled dose-response study. The doses of recombinant human GH ranged from 0.33-3.0 IU/m(2) . day. During GH treatment, dose reduction was necessary because of side-effects in 18 of 46 patients, i.e. in 18% of the patients receiving a maintenance d ose of 1 IU/m(2) . day, in 35% of the patients receiving a dose of 2 I U/m(2) . day, and in 67% of the patients receiving a dose of 3 IU/m(2) . day. In the untreated state, serum levels of all three markers were below the normal range in 90% of the patients. The rise in serum mark er concentrations during the first month of treatment was dose depende nt. Significant increases in IGF-I, IGFBP-3, and ALS levels were obser ved with a dose as low as 0.33 IU/m2 . day. The minimal GH dose requir ed for normalization of the serum IGF-I concentration was 0.66 IU/m(2) . day, and it was 1.0 IU/m(2) . day for ALS and IGFBP-3. In patients receiving 2.0 IU/m(2) . day, the mean serum IGF-I concentration rose t o an abnormally high level, whereas at this dose, the mean IGFBP-3 and ALS levels were not different from normal. The lower sensitivity of I GFBP-3 and ALS to GH doses in the high range was also apparent during long term treatment. The number of patients who developed IGFBP-3 or A LS levels that exceeded the upper normal limit was substantially small er than the number of patients with elevated IGF-I concentrations (2, 8, and 19 of 46 patients, respectively). In conclusion, serum IGF-I ap pears to be the preferred biochemical marker for the detection of GH e xcess in adults receiving GH replacement therapy, because it is more s ensitive than IGFBP-3 and ALS to GH doses in the high range. If normal ization of the serum IGF-I concentration is taken as the criterion for optimal GH replacement therapy, the predicted optimal GH dose for GHD men 20-40 yr old is 1.4 IU/m(2) . day, and the 95% confidence interva l is 1.2-1.6 IU/m(2) . day.