Childhood onset growth hormone deficiency (CO-GHD) may contribute to low bone mass and alterations to body composition. This thesis consists of a series of studies utilising dual-energy X-ray absorptiometry (DXA), peripheral quantitative computerized tomography (pQCT) and biochemical assessment of bone health and body composition of CO-GHD. In addition, metabolic profiles, glucose metabolism as well as quality of life have been studied in these subjects. Furthermore, an interventional study of weight bearing exercise (WBE) was performed to explore its role in influencing the bone health of children and adolescents with CO-GHD.
Chapter 1, relevant literature reviews explore: bone structure, growth, development and strength; GH/IGF-1 system and its actions; CO-GHD and its impacts during childhood and transition; and WBE and its mechanism and impacts on bone health. Chapter 2 presents the rationale and specific aims of this thesis.
Chapter 3, a retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005-2013 were reviewed. Of the 130, 74/130(57%) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74(82%) remained GHD with 51/74(69%) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Despite clinical guidelines, there was significant variation in the management of CO-GHD in young adulthood across Scotland.
Chapter 4, a cross-sectional control study of bone DXA measurements in (n=21) subjects with CO-GHD treated with rhGH and had attained final height from 2005 to 2013 in a single tertiary paediatric centre compared to (n= 21) heights /age matched healthy controls. By applying different models of DXA adjustment, our analysis revealed lower TB-BMC for bone area in males with CO-GHD and lower LS-BMAD SDS in females with CO-GHD compared to matched controls. In addition, subjects with CO-GHD had lower LM for height and higher FM for height compared to controls, and this was more pronounced in males than females (p=0.04). The time of onset and aetiology of CO-GHD have a larger influence on accrual of bone mass in these patients. These findings indicate that adolescents with CO-GHD have a low bone mass, despite prior long term rhGH replacement therapy.
In chapter 5, we investigated bone health of subjects with CO-GHD at time of initial evaluation and retesting at final height. A total of 25 children (first time assessment group) undergoing GH stimulation tests for investigation of short stature (naive GHD-15, normal-10), and 11adolescents with CO-GHD (retesting group) undergoing biochemical re-evaluation at final height after withdrawal of rhGH therapy (persistent GHD-7, GH-sufficient-4) were recruited from Royal Hospital for Children between 2012-2013. By using further bone health assessment methods in addition to DXA (including p.QCT, mechanography, bone profiles and biomarkers), the bone density and body composition did not differ when we compared GHD to matched height but normal GH at initial evaluation and retesting. However, naive GHD had lower muscle force as assessed by mechanography compared to the normal. In addition, bone resorption biomarker CTX was significantly higher in naive GHD vs. normal and that was significantly correlated to PTH levels in both first time assessment and retesting groups. Our results suggest that muscle force and serum PTH may be important determinants of bone health in subjects with CO-GHD.
Chapter 6 investigates lipids, adipokines (leptin- adiponectin- resistin) and glucose homeostasis and their relationship with bone and body composition in children and adolescents with CO-GHD at times of initial evaluation and retesting at final height (same population as chapter 5). Lipid profiles, adipokines and glucose homeostasis were not different between those with GHD and those who had normal GH levels across the groups of first time assessment and retesting. In the retesting group, those who were older at the time of diagnosis of CO-GHD with a shorter duration of rhGH therapy were more likely to have higher cholesterol(r=0.9, p<0.001), leptin (r=0.8, p<0.001), and lower osteoclacin (r=-0.7, p=0.01) at final height. Leptin levels correlated positively with osteocalcin at diagnosis (r=0.51, p=0.01) but inversely at retesting (r=-0.91, p<0.01). The conclusion was that the timing and duration of childhood rhGH therapy might influence adiposity parameters and bone metabolism in subjects with CO-GHD.
In chapter 7 the study participants of chapter 5 were asked to complete either Short Form-36 (SF-36) or Adult Growth Hormone Deficiency Assessment (AGHDA) quality of life (QoL) questionnaires at the time of assessment of their GH axis. Our analysis showed that the overall QoL was not altered in children with naive GHD with a total score of SF-36 [93 (77, 96) naive GHD vs. 90 (84, 93) normal, P=0.56] (higher scores reflect better QoL). However, naive GHD had less energy and vitality scores compared with normal (75 (65, 100) vs. 95 (65,100) respectively, p=0.04), when the normal scored lower in the subscale of emotional well-being compared to those with naive GHD (78 (55, 84) vs. 90 (68, 96) respectively, p<0.001). In the retesting group, those with persistent GHD scored better in the AGHDA than GH sufficient (6 points (2, 8) vs. 9 points (7, 17) respectively, though not significant (p= 0.10) (higher scores reflect poorer QoL). Unexpectedly, subscale analysis showed that GH-sufficient subjects significantly lacked energy and complained of tiredness compared to those who were confirmed to have persistent GHD (5 points (3, 6) vs. 1 point (0, 1) respectively, p= 0.03). Further studies to validate QoL specific instruments in this population are needed with greater insight to elucidate factors that modify the relationship between GH status and QoL in children and adolescents.
Chapter 8 was a prospective intervention, randomised controlled study of 14 subjects among the first time assessment group (GHD-10, normal-4) and five subjects with CO-GHD among retesting group (persistent GHD-4, GH-sufficent-1). Subjects were randomised into either an exercise intervention group (EX) (25 jumps off 25 cm platform step/ three days /week for six months) or a control, in addition to rhGH being prescribed. The results of this study were limited by the small sample size and poor compliance. Therefore, there were insufficient data to recommend the use of weight bearing exercise in the absence of rhGH in children and adolescents with CO-GHD. Further studies with adequate sample size that can more rigorously exam the optimal exercise interventions are needed.
Chapter 9 discusses the main findings of each chapter in this thesis and outlines potential limitations of the thesis methodology, and some important and interesting areas for future research in children and adolescents with CO-GHD
