Dose titration and patient selection increases the efficacy of GH replacement in severely GH deficient adults

OBJECTIVE Previous studies of GH replacement in adults have used unselected cohorts of GH deficient (GHD) adults and weight-based dosing regimens resu lting in supraphysiological serum IGF-I levels and a high frequency of side -effects and withdrawal from these studies. By choosing patients with a hig h level of morbidity at baseline and using a low dose GH titration regimen we aimed to avoid over-replacement and increase the efficacy of treatment. DESIGN An open study of GH replacement, initiating treatment with a dose of 0.8 U/day and titrating the dose by 0.4 U increments to normalize the IGF- I SDS between - 2.0 and + 2.0 SD of the age-related normal range. PATIENTS 65 severely GHD patients (peak GH < 9 mU/ I to provocative testing ), 25 males, of mixed adult and childhood-onset and mean age 38.7 (range 17 -72) years. Inclusion criterion was that of subjectively poor quality of li fe on clinical interview. MEASUREMENTS Height, weight, waist and hip circumference were measured to a llow calculation of body mass index (BMI) and waist-hip ratio (WHR). Bone m ineral density (BMD) was measured by dual X-ray absorptiometry (DEXA). Seru m haemoglobin A1C (Hb(A1C)), lipid profile and insulin like growth factor 1 (IGF-I) were measured. The Psychological General Well-Being Schedule (PGWB ) and Adult Growth Hormone Deficiency Assessment (AGHDA) self-rating questi onnaires (SRQ) were used to assess quality of life. RESULTS Baseline characteristics were consistent with those previously desc ribed in severely GHD adults; mean IGF-I SDS - 2.4 (+/- 2.7), BMI 28.8 (+/- 5.4) kg/m(2), total cholesterol 6.17 (+/- 1.2) mmol/l, reduced BMD z-score s at the lumbar spine (-0.8 +/- 1.2) and femoral neck (-0.44 +/- 1.4), and SRQ scores considerably lower than reported in previous studies of GH defic ient adults and normal controls. Following initiation of GH serum IGF-I SDS was increased significantly from baseline to a mean level of 0.15 +/- 2.7 (P<0.001) and 0.31 +/- 2.0 (P<0.0 01) at three and eight months, respectively. The mean PGWB score increased from 59.7 +/- 19.9 to 75.8 +/- 15.0 (P<0.001) and 73.7 +/- 19.5 (P = 0.001) at three and eight months, respectively. An increase of 14 points represen ts the largest improvement in quality of life, using this index, that has b een reported in GHD adults. The mean AGHDA score also demonstrated consider able improvement, falling from 15.3 +/- 6.0 to 10.4 +/- 6.2 (P<0.001) and 9 .8 +/- 6.5 (P<0.001) at three and eight months, respectively. The changes o bserved in both the PGWB and AGHDA scores between baseline and at both thre e and eight months were shown to correlate significantly with the respectiv e baseline score. A significantly greater improvement was observed in the P GWB following GH replacement in those with a baseline PGWB score of <60 tha n in those with a score >60. This observation was significant at both three (27.1 vs 6.7, P = 0.0001) and eight (25.6 vs 3.3, P = 0.0003) months. All PGWB subscales showed significant improvement though that of vitality was o f greatest magnitude. A strong correlation was observed between the generic and disease-specific SRQ (r= - 0.73, P< 0.001). CONCLUSIONS The observed improvement in quality of life in GH deficient adu lts is proportional to the degree of impairment before commencing therapy. The use of low-dose titration and selection of a population with greater mo rbidity reduces the occurrence of over-replacement and increases the effica cy of treatment. This allows direction of resources to those in greatest ne ed.