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GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.Columb, Breeda; Smethurst, Linda E; Mukherjee, Annice; Jostel, Andreas; Shalet, Stephen M; Murray, Robert D; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-02)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.
Partial Growth Hormone Deficiency is Associated With an Adverse Cardiovascular Risk Profile and Increased Carotid Intima-Medial Thickness.Murray, Robert D; Wieringa, Gilbert E; Lawrance, Jeremy A L; Adams, Judith E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-12-18)Abstract. Objective: To quantify the relative prevalence of surrogate markers of vascular risk in adults with partial GHD (GH-insufficiency; GHI) Context: Hypopituitary adults with untreated GHD have an excess vascular mortality and demonstrate clustering of adverse vascular risk factors. The vascular risk profile of GHI adults have yet to be comprehensively studied. Design: A cross-sectional case controlled study. Patients: 30 GHD adults, 24 GHI, and 30 age and sex-matched controls. GHI adults were defined biochemically using two GH stimulation tests (peak GH 3-7mug/l). Measurements: Serum lipids and apolipoproteins, PAI-I, CRP, Lp(a), fibrinogen, blood pressure and carotid IMT. Results: IGF-I levels of GHI adults were lower than controls (373+/-123 vs. 295+/-104mug/l; P<0.001). TC, LDL-C, and TG values were consistently between those of, but not significantly different from, GHD and control subjects. GHI adults showed significantly elevated PAI-I levels (80 [13-98] vs. 50.5 [3-98]ng/ml; P=0.01), though no difference in CRP, Lp(a), and fibrinogen levels compared with control subjects. No differences in systolic or diastolic BP were shown between study groups. In parallel with the increased vascular risk profile of GH-insufficient adults, carotid IMT was significantly increased (0.503+/-0.08 vs. 0.578+/-0.130mm; P=0.02). TC, LDL-C, WHR, truncal FM, and IMT correlated with IGF-I levels and GH status. TG, K(ITT), and PAI-I additionally correlated with GH status, but not IGF-I levels. Conclusion: GHI adults are at elevated vascular risk, reflected by adverse surrogate markers and increased carotid IMT. The surrogate risk marker profile parallels GHD adults, but is less divergent from that observed in healthy individuals. No data are yet available as to whether these anomalies will be reflected in an increased vascular mortality in GHI adults.
Serum vascular endothelial growth factor (VEGF) is elevated in GH deficient adults.Murray, Robert D; Randeva, Harpal S; Lewandowski, Krzysztof C; Komorowski, Jan; Lawrance, Jeremy A L; Adams, Judith E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. Robert.Murray@leedsth.nhs.uk (2011-04)GHD adults exhibit a number of adverse surrogate markers of vascular risk culminating in excess vascular morbidity and mortality. Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of a number of vascular morbidities. Furthermore, serum levels decrease following GH replacement in GHD adults, though it remains unclear if levels are significantly elevated in untreated individuals.