GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

BACKGROUND: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSION: 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.

Interdependence of lean body mass and total body water, but not quality of life measures, during low dose GH replacement in GH-deficient adults.

Lean body mass (LBM) and total body water (TBW) are reduced in GH-deficient (GHD) adults and alter with GH replacement. Whether these parameters are interdependent and whether alterations in their homeostasis contribute to the perceived quality of life (QOL) deficit in GHD remains unclear. In this study, IGF-I, body composition by whole-body dual-energy X-ray absorptiometry, TBW by deuterium dilution (D(2)O) and two validated QOL instruments - psychological general well-being schedule (PGWB, generic, 6 domains; lower score worse QOL) and assessment of GH deficiency in adults (AGHDA, disease orientated; higher score worse QOL) were studied at baseline and after 3 and 6 months of GH replacement in thirty GHD adults. Patients with diabetes insipidus, and cardiac and renal failure were excluded. Median age-adjusted IGF-I standard deviation score increased from -3.40 (-6.40 to -1.60) to -0.2 (-1.88 to 0.78) (P < 0.0001) at a median daily GH dose of 0.4 mg. During treatment, LBM increased from 47.4 +/- 10.7 kg at baseline to 49.5 +/- 10.8 kg at 6 months (P = 0.0008), and fat mass decreased from 28.0 +/- 12.1 kg at baseline to 27.2 +/- 12.6 kg at 6 months (P = 0.0004). A non-significant trend towards an increase in TBW was observed (mean 1.7 kg, P = 0.08). The PGWB score increased from 62.9 +/- 20.6 to 73.7 +/- 21.7 (P = 0.0006). The AGHDA score decreased from 13.7 +/- 7.3 to 8.75 +/- 7.75 (P = 0.0002). At each time point, a linear correlation between LBM and TBW was demonstrated, defined by TBW = (0.972 x LBM)-10.6. However, only a weakly positive correlation existed between the percentage changes in these variables (R = 0.40, P = 0.04). No correlations were demonstrated between QOL measures and body composition. The change in LBM with physiological GH replacement correlates weakly with change in TBW, therefore factors other than TBW may also contribute to the LBM changes. Improved QOL with GH replacement is not explained by favourable changes in body composition.

Reassessment of growth hormone status is required at final height in children treated with growth hormone replacement after radiation therapy.

The most appropriate way to manage GH replacement in the transition period to adulthood in children treated with GH for GH deficiency (GHD) is controversial. The Growth Hormone Research Society suggests that the retesting of GH status at final height (FH) is unnecessary in the presence of severe organic GHD, and cranial irradiation falls into this etiological category. This recommendation has never been validated. To investigate whether patients diagnosed in childhood as GHD secondary to irradiation require retesting after FH, GH status has been reassessed in a large cohort of irradiated children treated with GH during childhood. Seventy-three children underwent biochemical assessment of GH status after irradiation and again at FH after GH therapy had been discontinued; 66 and 67 of the 73 patients underwent two provocative tests at the two time points, respectively. The characteristics of the cohort include a median age at irradiation of 5 yr (range, 1-11 yr), a median biological effective dose (BED) of irradiation to the hypothalamic pituitary axis of 54 Gy (range, 23-82 Gy), and a median time of GH status reassessment after FH of 0.4 yr (range, 0-8.4 yr). During childhood, patients with all degrees of GHD (peak GH responses to provocative test < 6.7 ng/ml) are treated, whereas in adulthood, only patients with severe GHD (peak GH responses to provocative test < 3 ng/ml) are considered for GH replacement. GH status has been grouped as follows: group 1, peak GH less than 3 ng/ml to both tests (severe GHD); group 2, one test with a peak GH less than 3 ng/ml and the other test with a peak of 3 ng/ml or greater; group 3, peak GH of 3-6.7 ng/ml to both tests; group 4, one test with a peak GH of 3-6.7 ng/ml and the other test with a peak of more than 6.7 ng/ml; and group 5, peak GH more than 6.7 ng/ml to both tests (normal GH status). In childhood, the number of patients in groups 1, 2, 3, and 4 were 33, 22, 17, and one, respectively. At retesting, severe GHD was diagnosed in 21 (64%) of 33 patients who were diagnosed in childhood with severe GHD (group 1) and 17 (44%) of 39 patients who were diagnosed in childhood with moderate GHD (groups 2 and 3). In total, 35 (48%) of 73 patients in the whole cohort and 12 (36%) of 33 patients with severe GHD in childhood did not fulfill the severe GHD biochemical criteria for GH replacement in adulthood. Using multiple linear regression, GH status at retesting is predicted by BED, age at irradiation, and use of chemotherapy. In conclusion, the diagnosis of severe GHD in childhood secondary to irradiation should not be taken as irrefutable evidence of permanent severe organic GHD, and our recommendation is that retesting of GH status at FH should be mandatory.

A new sustained-release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile.

OBJECTIVE: Adult GH replacement is currently given by daily subcutaneous (sc) injections. Recently, sustained-release (SR) preparations of GH have been developed, the preparations being characterized by a dominant early release, resulting in supraphysiological early GH peaks, and a rapid decline thereafter. We present data on a new SR GH preparation. DESIGN: Phase I/II study of hGH-Biosphere(R) (SkyePharma AB, Malmo, Sweden), a new SR preparation of recombinant human GH in amylopectin microspheres coated with polylactide-coglycolide. PATIENTS: Eight adults with severe, untreated GH deficiency (stimulated GH peaks between < 1 and 1.7 microg/l), aged 36.1 years (range 22-49 years) in good general health. MEASUREMENTS: Pharmacokinetic (PK), pharmacodynamic (PD) and safety data over a period of 28 days. RESULTS: The systemic and local tolerability of the drug was satisfactory, and no serious adverse events occurred. PK analysis showed a smaller early serum hGH peak followed by a broad sustained second peak of hGH (C(max) 1.20 microg/l at 7.2 days), and hGH levels were maintained above baseline for at least 14 days. The mean GH level never exceeded 1.1 microg/l, making the GH fluctuations comparable to continuous sc infusion. Resultant IGF-I concentrations were characterized by sustained elevation at a level near C(max) of 103 microg/l (at t(max) of 9.7 days), equal to an SD score of +0.8. IGF-I generation per administered GH was more efficient compared with reports of other SR preparations. CONCLUSION: hGH-Biosphere(R) is a well-tolerated SR GH preparation with superior efficacy in achieving target IGF-I levels without causing supraphysiological GH concentrations. Our data suggest the suitability of this preparation for longer-term trials in adults with injection frequencies of no more than once every 2-3 weeks.