A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults.

Division of Internal Medicine, Department of Medicine and Care, Faculty of Health Sciences, Universitetssjukhuset, S-581 85 Linköping, Sweden.
European Journal of Endocrinology (Impact Factor: 3.69). 08/2002; 147(1):49-57. DOI: 10.1530/eje.0.1470049
Source: PubMed

ABSTRACT To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.
Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.
Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.
In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Females secrete 2-3 -fold greater amounts of GH compared with males despite maintaining similar IGF-I levels. IGF-I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF-I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood-onset (CO) have lower basal IGF-I SDS and require higher GH maintenance doses compared with adult-onset (AO) patients with GHD of equal severity. We hypothesised CO-GHD adults to be less sensitive to GH than AO-GHD patients. In a single site study we analysed the incremental change in IGF-I (DeltaIGF-I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide DeltaIGF-I/mg GH because of slight variances in initial GH dose. Following GH replacement DeltaIGF-I was 230 +/- 245 and 356 +/- 278 ng/ml/mg GH in females and males, respectively (P = 0.01). In CO and AO patients DeltaIGF-I was 282 +/- 206 and 294 +/- 292 ng/ml/mg GH, respectively (P = 0.83). Further analysis after stratification by both gender and timing of onset of GHD showed DeltaIGF-I was 226 +/- 164, 324 +/- 228, 231 +/- 268, and 373 +/- 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0.03; CO males vs. CO females, P = 0.17; AO males vs. CO males, P > 0.05; AO females vs. CO females, P > 0.05). Multiple linear regression with DeltaIGF-I as the dependent variable and age, gender, BMI, baseline IGF-I level, and timing of onset as independent variables showed DeltaIGF-I to be dependent on gender alone (R = 0.28, P = 0.004). Age (P = 0.44), BMI (P = 0.54), baseline IGF-I level (P = 0.63) and timing of onset (P = 0.61) had no effect on DeltaIGF-I. We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF-I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.
    Clinical Endocrinology 09/2008; 70(2):281-6. DOI:10.1111/j.1365-2265.2008.03354.x · 3.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A sustained-release recombinant human GH formulation, LB03002, has been recently developed, with pharmacokinetics and pharmacodynamic activity appropriate for once-weekly administration. LB03002 is a long-acting GH that is administered once a week by s.c. injection. This study evaluated efficacy and safety of LB03002 in adult patients with GH deficiency. A total of 152 patients were randomized to receive LB03002 or placebo once weekly for 26 wk. Changes in body composition were evaluated from DXA (dual-energy x-ray absorptiometry). IGF-I was assessed at each study visit. Safety was assessed from adverse events, glucose homeostasis, and antibody development. IGF-I increased significantly (P < 0.001) with LB03002 and remained unchanged with placebo. Mean fat mass (FM) decreased by 1.052 kg [95% confidence interval (CI) = -1.614 to -0.491] in the LB03002 group vs. an increase of 0.570 kg (95% CI = -0.205-1.345) in the placebo group; treatment difference was 1.622 kg (95% CI = -2.527 to -0.717; P < 0.001). FM change was mainly due to decreased trunk fat. Least square mean treatment difference was 1.032 kg (95% CI = -1.560 to -0.515; P < 0.001). LBM (lean body mass) was significantly increased with LB03002 vs. placebo (least square mean difference was 1.393 kg; 95% CI = 0.614-2.171; P < 0.001). No concerning safety issues arose during the study. Weekly GH replacement with the sustained-release preparation LB03002 in adults significantly reduced FM over 6 months and was well tolerated.
    The Journal of Clinical Endocrinology and Metabolism 03/2011; 96(6):1718-26. DOI:10.1210/jc.2010-2819 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We studied the effects of individualised growth hormone (GH) substitution, aiming at normal insulin-like growth factor I (IGF-I) levels, on biomechanical output and surface electromyogram (EMG) of isokinetic muscle strength and endurance performance in 18 hypopituitary adults and compared with 17 matched healthy controls. The muscle function tests consisted of isokinetic contractions of the right knee extensors, from which torque and EMG were recorded. Three patients were excluded from the final analysis of the muscle function tests due to technical errors and one control subject moved from the area during the study. We found that GH-deficient adults without GH substitution were weaker and had less endurance than healthy control subjects. At the group level, plasma levels of IGF-I were normalised but generally no significant effects upon biomechanical output and EMG were found after dose titration and 6 months of a constant GH dose. However, subjects with the largest changes in IGF-I had significantly better biomechanical output and EMG compared to those with small changes in IGF-I. This finding may indicate that the net increase in IGF-I levels is critical for improvements in biomechanical output, EMG and perception of fatigue to occur.
    Arbeitsphysiologie 12/2003; 90(5-6):496-504. DOI:10.1007/s00421-003-0895-2 · 2.30 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014