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Dose titration and patient selection increases the efficacy of GH replacement in severely GH deficient adults
R D Murray1, C J Skillicorn, S J Howell
1Department of Endocrinology, Christie Hospital, Manchester, UK.
Insights
This study shows that a low-dose growth hormone (GH) replacement regimen in severely GH deficient (GHD) adults with poor quality of life significantly improves well-being. This approach avoids over-replacement and enhances treatment efficacy for those most in need.
Area of Science:
- Endocrinology
- Metabolic Disorders
- Clinical Research
Background:
- Previous growth hormone (GH) replacement studies in adults used unselected cohorts and weight-based dosing, leading to supraphysiological IGF-I levels, side effects, and high withdrawal rates.
- A tailored, low-dose GH titration regimen was hypothesized to improve efficacy and reduce adverse events in GH deficient (GHD) adults.
Purpose of the Study:
- To evaluate the efficacy and safety of a low-dose GH titration regimen in severely GHD adults with a high baseline morbidity and poor quality of life.
- To assess the impact of GH replacement on quality of life, body composition, and metabolic parameters in this selected patient population.
Main Methods:
- An open-label study involving 65 severely GHD adults (peak GH < 9 mU/l) with subjectively poor quality of life.
- Initiated GH treatment at 0.8 U/day, titrating to normalize IGF-I SDS between -2.0 and +2.0.
- Assessed quality of life using the Psychological General Well-Being Schedule (PGWB) and Adult Growth Hormone Deficiency Assessment (AGHDA) questionnaires.
Main Results:
- GH replacement significantly increased serum IGF-I SDS from -2.4 at baseline to 0.15 at 3 months and 0.31 at 8 months (P < 0.001).
- Mean PGWB scores improved significantly from 59.7 to 75.8 at 3 months and 73.7 at 8 months (P < 0.001).
- AGHDA scores also showed significant improvement, decreasing from 15.3 to 10.4 at 3 months and 9.8 at 8 months (P < 0.001).
Conclusions:
- Low-dose GH titration in selected GHD adults with high morbidity leads to significant improvements in quality of life.
- This regimen effectively normalizes IGF-I SDS, reduces over-replacement, and enhances treatment efficacy, particularly in patients with lower baseline well-being scores.
- The findings support a targeted approach to GH replacement, directing resources to patients with the greatest need and highest potential for benefit.
Objective:
Previous studies of GH replacement in adults have used unselected cohorts of GH deficient (GHD) adults and weight-based dosing regimens resulting in supraphysiological serum IGF-I levels and a high frequency of side-effects and withdrawal from these studies. By choosing patients with a high 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/l 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 life on clinical interview.
Measurements:
Height, weight, waist and hip circumference were measured to allow calculation of body mass index (BMI) and waist-hip ratio (WHR). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DEXA). Serum haemoglobin A1C (HbA1C), 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 questionnaires (SRQ) were used to assess quality of life.
Results:
Baseline characteristics were consistent with those previously described in severely GHD adults; mean IGF-I SDS - 2.4 (+/- 2.7), BMI 28.8 (+/- 5. 4) kg/m2, total cholesterol 6.17 (+/- 1.2) mmol/l, reduced BMD z-scores 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 deficient 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 < 0.001) 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 represents the largest improvement in quality of life, using this index, that has been reported in GHD adults. The mean AGHDA score also demonstrated considerable 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 observed in both the PGWB and AGHDA scores between baseline and at both three and eight months were shown to correlate significantly with the respective baseline score. A significantly greater improvement was observed in the PGWB following GH replacement in those with a baseline PGWB score of < 60 than 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 of 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 adults is proportional to the degree of impairment before commencing therapy. The use of low-dose titration and selection of a population with greater morbidity reduces the occurrence of over-replacement and increases the efficacy of treatment. This allows direction of resources to those in greatest need.