Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency

objective To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography. subjects Thirty‐nine patients (17 women, 22 men, aged 25–70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF‐1 levels, and 39 sex‐, age‐ and body mass index (BMI)‐matched healthy controls. results Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0·88 ± 0·26 vs. 0·69 ± 0·14 mm, P < 0·001), and systolic and diastolic peak velocity (P < 0·001) compared to controls. Eight patients (18%) and one control (2·1%, P = 0·04) had well‐defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0·78, P < 0·001). In both controls (r = ?0·82; P < 0·0001) and patients with GHD (r = ?0·84, P < 0·0001), serum IGF‐1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH‐deficient patients were total cholesterol levels (t = 5·2, P < 0·001), followed by disease duration (t = 2·4, P = 0·02), while in controls the variables most significantly related to IMT were IGF‐1 levels (t = ?9·9, P < 0·001), followed by low density lipoprotein (LDL)‐cholesterol levels (t = ?2·3, P = 0·02). Compared to patients with normal IGF‐1 levels, those with low IGF‐1 levels had lower high density lipoprotein (HDL)‐cholesterol levels (1·0 ± 0·2 vs. 1·3 ± 0·2 mmol/l, P = 0·0002), and higher glucose (54·3 ± 6·1 vs. 48·9 ± 5·9 mmol/l, P = 0·008), insulin (25·2 ± 6·8 vs. 18·8 ± 6·0 mUl/l, P = 0·004), total cholesterol (7·1 ± 1·1 vs. 4·9 ± 0·6 mmol/l, P < 0·0001), total/HDL‐cholesterol ratio (7·2 ± 1·8 vs. 3·9 ± 0·7, P < 0·0001), fibrinogen levels (319·8 ± 56·9 vs. 241·8 ± 53·0 mg/dl, P < 0·0001) and mean IMT at common carotid arteries (1·05 ± 0·25 vs. 0·69 ± 0·07 mm, P < 0·0001). Atherosclerotic plaques were found only in GH‐deficient patients with low IGF‐1 levels. conclusions GH‐deficient patients have alterations in lipid profile with an increase in the total/HDL‐cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF‐1 deficiency have increased IMT.     

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 (ΔIGF‐I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide ΔIGF‐I/mg GH because of slight variances in initial GH dose. Results Following GH replacement ΔIGF‐I was 230 ± 245 and 356 ± 278 ng/ml/mg GH in females and males, respectively (P = 0·01). In CO and AO patients ΔIGF‐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 ΔIGF‐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 ΔIGF‐I as the dependent variable and age, gender, BMI, baseline IGF‐I level, and timing of onset as independent variables showed ΔIGF‐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 ΔIGF‐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.     

Bone demineralization in adult thalassaemic patients: contribution of GH and IGF-I at different skeletal sites

Background and objective GH and IGF‐I exert an important role in the control of bone formation, as shown by decreased bone mineral density and increased fracture risk in adult hypopituitary patients untreated for GH deficiency (GHD). Different degrees of bone demineralization are frequently reported in patients affected by β‐thalassaemia. Considering the high prevalence of GHD recently observed by our group among adult thalassaemic patients, we elected to study the possible role of GH–IGF‐I abnormalities in the pathogenesis of the osteopenia/osteoporosis of this disease. Design Sixty‐four adult thalassaemic patients (49 with thalassaemia major and 15 with thalassaemia intermedia, 23 men and 41 women, aged 31·4 ± 6·8 years) were studied. Methods Bone mineral density was assessed by dual energy X‐ray absorptiometry at lumbar spine in 62 patients and at proximal femur in 58. All patients underwent GHRH (1 µg/kg as an i.v. bolus) plus arginine (0·5 g/kg as a 30‐min i.v. infusion) testing. Severe GHD was defined by GH peaks < 9 µg/l, whereas partial GHD was defined by GH peaks ranging from 9 to 16·5 µg/l. Blood samples for IGF‐I measurement were collected. Results Lumbar osteoporosis and osteopenia were demonstrated in 46/62 (74·1%) and 14/62 (22·5%) patients, respectively. Femoral osteoporosis and osteopenia were documented in 22/58 (37·9%) and 32/58 (55·1%) patients, respectively. Severe GHD was demonstrated in 16/64 patients (25%), while 11 additional patients (17·1%) displayed partial GHD. IGF‐I standard deviation score (SDS) was low, that is, below –1·88, in the majority (54·6%) of patients. Lumbar T‐score values were not correlated with either GH peaks or IGF‐I SDS values. Femoral T‐score values were positively correlated with GH peaks (r = 0·38, P < 0·005) and IGF‐I SDS values (r = 0·39, P < 0·005). Multiple regression analysis pointed to both GH peak and IGF‐I SDS as predictors of femoral T‐score. Furthermore, mean femoral T‐score was significantly lower in patients with severe GHD than in those with normal GH secretion (–2·94 ± 0·25 vs.–2·15 ± 0·12, P < 0·01). Conclusion This study, while confirming the high prevalence of both osteopenia/osteoporosis and somatotropin–somatomedin deficiency in adult thalassaemic patients, indicates that defective GH secretion and diminished serum IGF‐I levels may contribute to femoral demineralization in these patients. Further studies are worth carrying out to evaluate the efficacy of biosynthetic GH administration on bone abnormalities of GH‐deficient thalassaemic adults.     

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD)

Objective At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF‐I within the reference range. It is unclear whether in such patients serum IGF‐I levels are regulated by factors other than GH. Design and patients We performed a double‐blind, randomized, placebo‐controlled, cross‐over study to investigate the effect of the GH receptor antagonist – pegvisomant (20 mg daily for 14 days) on GH and IGF‐I levels in three cohorts: patients with GHD and a normal IGF‐I (NORMS); patients with GHD and a low IGF‐I (LOWS) and healthy volunteers (CONS). Results Pegvisomant decreased IGF‐I in CONS and NORMS [158·5 (101–206) vs. 103 (77–125) µg/l, P < 0·01; 124 (81–136) vs. 95 (51–113) µg/l, P < 0·01 respectively], but not in LOWS [31 (< 31–32) vs. 34·5 (< 31–38) µg/l], and this was associated with an increase in mean 24 h GH in CONS [0·49 (0·12–0·89) to 1·38 (0·22–2·45) µg/l (P = 0·03)] and in NORMS [69 (0–320)% from 0·1 (< 0·1–0·13) to 0·17 (0·11–0·42) µg/l (P = 0·03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6·1 (0·8–9) vs. 20·4 (13·1–28·8) µg/l, P = 0·03; 0·4 (0·1–0·5) vs. 0·5 (0·3–0·6) µg/l, respectively], but not in LOWS. Conclusions These data indicate that patients with severe GHD with a normal IGF‐I are able to increase GH secretion in response to a pegvisomant‐induced fall in IGF‐I, whereas those with low IGF‐I levels are unable to increase GH secretion. Therefore circulating IGF‐I appears to be GH‐independent in GHD patients with a low IGF‐I, but remains partially GH‐dependant in GHD patients with a normal IGF‐I.     

Partial growth hormone deficiency in adults; should we be looking for it?

Quantitatively, GH secretion exists as a continuum in states ranging from good health through to hypopituitarism. Currently, GH replacement is considered only for adults designated as being severely GH deficient (GHD). In clinical practice the gold standard, on which the biochemical diagnosis of severe GHD is based, centres on the presence of two or more additional anterior pituitary hormone deficits. Cohorts of adults with partial GHD (Growth Hormone Insufficiency [GHI]) have been reported with adverse body composition changes, dyslipidaemia, insulin resistance, altered cardiac performance and increased carotid intima‐media thickness. The diagnosis of GHI in an individual patient, however, is extremely difficult because such patients rarely exhibit additional anterior pituitary hormone deficits, and the levels of GH‐dependent proteins, including IGF‐I, are normal in the majority. Currently, GH replacement therapy should only be considered in a patient characterized as GHI by dynamic GH testing in whom there is a plausible cause for hypopituitarism and in whom the IGF‐I level is pathologically low.     

Effects on metabolic variables after 12-month treatment with a new once-a-week sustained-release recombinant growth hormone (GH: LB03002) in patients with GH deficiency

Introduction GH substitution in GH deficiency (GHD) must be subcutaneously administered daily. A new sustained‐release formulation of GH (LB03002) has been developed, which has to be injected once a week. As a substudy to the phase III study, we performed this prospective study to evaluate the influence of LB03002 on metabolic variables and hormones. Methods Eleven patients with GHD [four women/seven men, 58 years (29–69 years)] without GH therapy were included in the study. Eight patients were treated with LB03002 for 12 months and three patients received placebo for 6 months followed by LB03002 for 6 months. A 3‐h oral glucose tolerance test (OGTT) was performed at study entry and at study end. Additionally, IGF‐I, cholesterol, LDL, HDL, triglycerides, leptin, ghrelin, HbA1c and C‐peptide were measured. Body composition was evaluated by dual‐energy X‐ray absorptiometry (DXA), and waist/hip ratio (WHR) and waist/height (WHtR) ratio were measured by tape and scale. Results Multiple of upper limit of normal (xULN) of IGF‐I (0·23 (0·09–0·4) vs 0·71 (0·4–1·04), P < 0·01), WHR (0·98 (0·86–1·04) vs 1·01 (0·86–1·05), P < 0·05) and ghrelin levels [119·8 ng/l (67·7–266·6) vs 137 ng/l (67–289·5), P < 0·05] were significantly higher, whereas fat mass (FM) [34·7% (20·4–49·2) vs 32·4% (16·7–48·5), P < 0·05] and leptin [11·2 μg/l (3·3–55·7) vs 7·05 μg/l (2·4–54·3), P < 0·05] were significantly lower at study end. Glucose, insulin, HOMA‐IR, ISI, HOMA‐β, C‐peptide and HbA1c during OGTT were not significantly different before and after GH substitution, neither were BMI, WHtR, bone mineral density and lipid variables. Conclusion Substitution with LB03002 showed statistically significant reduction in FM, which reduces leptin levels and increases ghrelin levels but does not seem to influence glucose and lipid metabolism.     

GH and IGF-I deficiency are associated with reduced loss of fat mass after laparoscopic-adjustable silicone gastric banding

Context GH secretion is reduced in obese subjects and increases after body weight loss. It is still unclear if changes in the GH/IGF‐I axis after laparoscopic‐adjustable silicone gastric banding (LASGB) are associated with changes of body composition. Objective To analyse the relationships between changes in the GH/IGF‐I axis and those of body weight and composition before and after LASGB. Design Observational, prospective. Setting University ‘Federico II’ of Naples (Italy). Patients Seventy‐two severely obese females (BMI: 44·9 ± 4·68; mean age: 33·1 ± 11·34 years) were studied. Main outcome measures GH peak after GHRH plus arginine test, IGF‐I, IGFBP‐3 and ALS levels, fat mass (FM) and free fat mass (FFM) (by Bioelectrical Impedance Analysis) at baseline and 6 months after LASGB. The change in percentage of individual variables was calculated as well as that of excess of body weight loss (EBWL%). The FM%, FFM% and EBWL% were correlated with peak GH and IGF‐I levels changes. Results At baseline, GH deficiency (GHD) (GH peak = 4·1 µg/l) was found in 22 patients (31%), 16 of them also had IGF‐I deficiency (< –2SDS). IGF‐I levels were inversely correlated with waist circumference (r = –0·72, P < 0·001) and FM% (r = –0·75, P < 0·001). Post‐LASGB the patients were classified as follows: group (1) GH and IGF‐I sufficient (n = 44; 61·1%); group (2) GH and IGF‐I deficient (n = 14; 19·4%) and group (3) GH sufficient and IGF‐I deficient (n = 14; 19·4%). The percentage changes of EWBL (P < 0·05, P = 0·051, respectively) and FM (P < 0·001, P < 0·01, respectively) were lower in groups (2) and (3) than in group (1). At the stepwise linear regression analysis, postoperative IGF‐I levels were the strongest determinant of percent changes of FM (P < 0·0001), of FFM (P = 0·009) and of EBWL (P < 0·0001). Conclusions IGF‐I levels is the most sensitive to unfavourable changes in body composition 6 months after LASGB making investigation of the somatotropic axis useful in the evaluation of bariatric surgery outcomes.     

The effects of growth hormone status on circulating levels of vascular growth factors

Background Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin‐2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology. Aim To investigate the effect of GH status on the circulating levels of angiogenic factors. Design We measured the levels of six endothelial growth modulators, four angiogenic growth factors and two inhibitors of angiogenesis in 35 untreated acromegalics, 36 untreated GH‐deficient subjects and 101 normal control subjects. Fifteen GH‐deficient subjects were also studied before and 1 year after treatment with GH. Results Mean angiogenin concentrations were increased in acromegaly and decreased in GH‐deficient subjects compared to control subjects. Endostatin levels showed a similar pattern although the elevated levels in acromegalic subjects did not achieve statistical significance. Angiogenin and endostatin levels both correlated significantly with IGF‐I levels (R = 0·61, P < 0·001 and R = 0·22, P < 0·01, respectively). The relationship between angiogenin and IGF‐I levels remained significant even after correction for gender, age, body mass index (BMI) and insulin resistance. There were no significant differences in the levels of HGF, VEGF, VEGF‐C or angiopoietin‐2 between the three groups. VEGF‐D levels were elevated in both acromegalic and GH‐deficient male subjects. A similar pattern was apparent in female subjects. After GH treatment, a significant reduction in VEGF‐D levels and a significant rise in endostatin levels were observed in GH‐deficient subjects. A nonsignificant increase in angiogenin levels was also observed. Conclusion These data indicate that significant perturbations in the levels of vascular growth modulators are present in both acromegaly and GHD. While changes in endostatin and angiogenin levels appear to correlate with IGF‐I levels, VEGF‐D levels show similar perturbations in both acromegaly and GHD. Further studies are required to determine the relationship of the perturbations to endothelial dysfunction in these conditions.     

The effect of growth hormone (GH) replacement on muscle strength in patients with GH‐deficiency: a meta‐analysis

Context/objectives GH replacement increases muscle mass and reduces body fat in growth hormone deficiency (GHD) adults. A recent meta‐analysis has demonstrated that this improvement in body composition is associated with improved exercise performance. The current meta‐analysis was carried out to determine whether high‐quality evidence exists to support a beneficial effect of GH replacement on strength. Design/methods An extensive Medline search/literature review identified eight studies with utilizable, robust data, involving 231 patients in nine cohorts. Previously unpublished data were sought from authors and obtained in two cases. All studies included were randomized, double‐blind, placebo‐controlled, of parallel or cross‐over design and of an average 6·7 months duration. Information was retrieved in uniform format, with data pertaining to patient numbers, study‐design, GH‐dose, mean age, IGF‐I levels and muscle strength measurements (isometric or isokinetic quadriceps strength) recorded. Data were analysed using a fixed‐effects model, utilizing continuous data measured on different scales. A summary effect measure (d_s) was derived for individual strength variables, whereas an overall summary effect was derived from the sum of all studies incorporating different variables; 95% CIs were calculated from the weighted variances of individual study effects. Results Analysis revealed no significant improvement, neither when all studies were combined (d_s = +0·01 ± 0·26) nor when measured individually (isometric quadriceps strength, d_s = +0·02 ± 0·32 and isokinetic quadriceps strength, d_s = 0·00 ± 0·45). Conclusions Evidence from short‐term controlled studies fails to support a benefit on muscle strength of GH replacement in GHD patients, which is likely to occur over a longer time‐course, as seen in open‐label studies.     

Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

Context Patients with congenital adrenal hyperplasia (CAH) because of 21‐hydroxylase deficiency have multiple vascular risk factors. Young adults with CAH have increased intima media thickness, but there have been no studies of vascular function and structure in children with CAH. Objective To establish whether children with CAH have reduced vascular function and increased carotid intima media thickness (cIMT) when compared to healthy and obese children. Design and Patients Cross‐sectional study of 14 patients (14·8 years ± 3·2, seven boys) with CAH secondary to 21‐hydroxylase deficiency compared to 28 obese and 53 healthy controls. Measurements All subjects had assessment of endothelial function flow‐mediated dilatation, (FMD), smooth muscle function glyceryl tri‐nitrate dilatation (GTN) and cIMT. Anthropometric data, resting blood pressure and biochemical variables were also measured. Results Congenital adrenal hyperplasia subjects had significantly reduced FMD (4·5 ± 3·0%vs 7·5 ± 5·2%; P = 0·04) and GTN (17·2 ± 1·6%vs 28·4 ± 8·4%; P < 0·001) when compared to controls and the impairment was comparable to the obese cohort. There was no significant difference in cIMT between groups. CAH subjects had increased homoeostasis model of assessment‐insulin resistance [HOMA‐IR 2·5 (0·2–2·9) vs 1·8 (0·5–4·2); P = 0·04], waist‐to‐height ratio (0·47 ± 0·05 vs 0·44 ± 0·04; P = 0·02) and higher systolic blood pressure Z score (0·29 ± 0·9 vs?0·24 ± 0·64, P = 0·01) compared to healthy controls but not when compared to obese controls. Conclusions Subjects with CAH have evidence of vascular dysfunction by adolescence.     

Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse

Context A method based on the two GH dependent markers, IGF‐I and procollagen III peptide (P‐III‐P) has been proposed to detect exogenously administered GH. As previous studies involved predominantly white European elite athletes, it is necessary to validate the method in other ethnic groups. Objective To examine serum IGF‐I and P‐III‐P in elite athletes of different ethnicities within 2 h of competing at national or international events. Design Cross‐sectional observational study. Setting National and International sporting events. Subjects 1085 elite athletes of different ethnicities. Intervention Serum IGF‐I and P‐III‐P were measured and GH‐2000 discriminant function score was calculated. Effect of ethnicity was assessed. Results In men, IGF‐I was 21·7 ± 2·6% lower in Afro‐Caribbeans than white Europeans (P < 0·0001) but there were no differences between other ethnic groups. In women, IGF‐I was 14·2 ± 5·1% lower in Afro‐Caribbeans (P = 0·005) and 15·6 ± 7·0% higher in Orientals (P = 0·02) compared with white Europeans. P‐III‐P was 15·2 ± 3·5%, 26·6 ± 6·6% and 19·3 ± 5·8% lower in Afro‐Caribbean (P < 0·0001), Indo‐Asian (P < 0·0001) and Oriental men (P = 0·001), respectively, compared with white European men. In women, P‐III‐P was 15·7 ± 4·7% lower in Afro‐Caribbeans compared to white Europeans (P =0·0009) but there were no differences between other ethnicities. Despite these differences, most observations were below the upper 99% prediction limits derived from white European athletes. All GH‐2000 scores lay below the cut‐off limit proposed for doping. Conclusions The GH‐2000 detection method based on IGF‐I and P‐III‐P would be valid in all ethnic groups.     

Effects of growth hormone replacement within the KIMS survey on estimated cardiovascular risk and predictors of risk reduction in patients with growth hormone deficiency

Objective There is growing evidence for an increased cardiovascular (CV) risk in untreated growth hormone deficiency of adults (GHD). We aimed at estimating CV risk with established algorithms before and during GH replacement in GHD and in healthy controls and at identifying predictors of risk reduction. Design A prospective, nested case‐control study. Patients We included 344 patients (44·7 ± 14·9 years) from the German Pfizer (formerly Kabi) International Metabolic Database (KIMS) cohort and included a healthy sex‐ and age‐matched control group from a primary care cohort. Measurements We calculated Framingham, Prospective Cardiovascular Münster Heart Study (PROCAM) and European Society of Cardiology (ESC) Score algorithms at all time points. In multivariate analyses, we analysed potential predictors of 2‐year reduction in CV risk, defined as a higher than median reduction in risk. Results In KIMS, the estimated 10‐year risks of CV events or CV mortality calculated with Framingham, PROCAM and ESC Score algorithms at baseline were 4·6%, 6·0% and 2·3%, respectively. These dropped to 2·4%, 4·8% and 0·8%, respectively, after 2 years of GH replacement (all P < 0·001 vs baseline) and returned to baseline levels after four years of GH replacement. In controls, the Framingham risk estimates were lower than in KIMS at baseline. All risk estimates increased during follow‐up and were significantly higher than in KIMS after four years (all P < 0·01). In backward‐selection models, high total cholesterol, low high‐density lipoprotein (HDL) cholesterol and male sex were significant predictors of response in most scores. Conclusion Two years of GH replacement decreased CV risk estimates approximately by half. Male sex, high total and low HDL cholesterol levels are potential predictors of good response.     

Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy

Objective Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow‐up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. Design Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. Patients Sixty‐one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2·5 ± 2·7 SD years before GH) (statin group – SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group – NSG) were studied. All patients were naïve or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4·4% NSG at baseline. Measurements Serum concentrations of total, high density lipoprotein (HDL)‐cholesterol, triglycerides and IGF‐I were measured centrally in all patients and LDL‐cholesterol was estimated using Friedewald's formula. Results The relative frequency of various statin use was simvastatin 52% (15·8 ± 8·1 mg, mean ± SD), atorvastatin 30% (14·4 ± 7·8 mg), pravastatin 9·8% (31·6 mg ± 13·9 mg), lovastatin 6·6% (17·5 ± 5 mg) and fluvastatin 1·6% (40 mg). Baseline serum total and LDL‐cholesterol (mean ± SD) were 5·2 ± 1·4 and 3·1 ± 1·3 mmol/l in SG and 5·8 ± 1·2 and 3·7 ± 1·0 mmol/l in NSG, respectively (P < 0·0001, SG vs. NSG). After 12 months GH replacement (SG: 0·32 ± 0·17 mg/day; NSG: 0·38 ± 0·1 mg/day) serum total and LDL‐cholesterol decreased by a mean (±SD) of 0·48 (± 1·25) mmol/l (P < 0·0004) and 0·53 (± 1·08) mmol/l (P < 0·0001) in SG and by 0·30 (± 0·89) mmol/l (P < 0·0001) and 0·28 (± 0·80) mmol/l (P < 0·0001) in NSG, respectively. There were no significant changes in HDL‐cholesterol or triglycerides in either group (SG vs. NSG: NS). A relationship between LDL‐cholesterol at baseline and the decrease in LDL‐cholesterol after 12 months GH was evident in both groups (SG: R = –0·54, P < 0·001; NSG: R = –0·4, P < 0·001) and a similar relationship for cholesterol was observed. Conclusions These data indicate that GH replacement exerts additional beneficial effects on lipoprotein profiles in patients on maintenance statin therapy, confirming that the effects of these interventions are complementary rather than exclusive.     

The effect of recombinant IGF-I on anterior pituitary function in healthy volunteers

OBJECTIVE Insulin-like growth factor-I is the mediator of many of the actions of GH and is a potent metabolic regulator. Recombinant IGF-I (rhIGF-I) is of potential value in the treatment of syndromes associated with either GH or insulin resistance. This study was designed to assess the effects of subcutaneous (s.c.) rhIGF-I on anterior pituitary function. DESIGN Double-blind, placebo controlled, randomized cross-over study. The interval between investigations was 2 weeks. SUBJECTS Twelve normal volunteers received on one occasion a single S.C. dose of 40 μg/kg rhIGF-I and on the other, placebo. MEASUREMENTS Circulating levels were measured, over 24 hours, of GH, LH, FSH, PRL, TSH, cortisol, ACTH, glucose, IGF-I, IGF-II, Insulin, C-peptide; IGF binding proteins by Western ligand blotting; total IGF bioactivity using FRTL-5 thyroid cells; and glucose by the glucose oxidase method. RESULTS Recombinant IGF-I Increased AUC for plasma IGF-I, measured by radioimmunoassay (rhIGF-I mean 7065 ± SEM 33 vs 3895 ± 204 μg/l, P < 0·0001) and IGF bioactivity (22·5 ± 3·4 vs 14·2 ± 1·8 U/ml, P < 0·001) but plasma IGF-II fell (9308 ± 403 vs 11052 ± 451 μg/l, P < 0·0001). There was no biochemical or clinical evidence of hypoglycaemia and no difference in mean glucose levels. No difference existed in AUC for GH, LH, FSH, ACTH and cortisol between rhIGF-I and placebo; additionally, pulse number and amplitude for GH and LH were unaffected. TSH fell following rhIGF-I (33·0 ± 3·36 vs 42·5 ± 5·98 mU h/l, P= 0·01). Both mean plasma C-peptlde (0·73 ± 0 06 vs 0·91 ± 0±05 nmol/l, P= 0·03), and insulin (10·81 ± 1·02 vs 15·36 ± 1·18 mU/l, P= 0·03) were lower following rhIGF-I. There was no change In IGFBPs. CONCLUSION A single injection of 40 μg/kg of subcutaneous rhIGF-I does not cause hypoglycaemia. IGF bioactivity was increased without inhibition of GH secretion. The only change observed in anterior pituitary function was a fall in plasma TSH.     

The relationship between reduced testosterone,stimulated growth hormone secretion and increased carotid intima‐media thickness in obese men

Objective Obesity is associated with reduced testosterone and growth hormone (GH). However, the interrelationship between these axes and their independent contributions to cardiovascular risk is unknown. The objectives of this study were to determine (1) the association between testosterone and GH in obesity, (2) whether excess adiposity mediates this association and (3) the relative contribution of reduced testosterone and GH to increased carotid intima‐media thickness (cIMT) in obesity. Design Fifty obese men were studied with GH‐releasing hormone–arginine testing, and morning free testosterone (FT) was measured by equilibrium dialysis. Metabolic, anthropometric and cardiovascular risk indices, including cIMT were measured. Twenty‐six normal weight men served as controls. Results Obese subjects demonstrated lower mean (±SEM) peak stimulated GH (5·9 ± 0·6 vs 36·4 ± 3·9 μg/l; P < 0·0001) and FT (0·41 ± 0·03 vs 0·56 ± 0·03 nmol/l; P = 0·0005) compared to controls. GH was significantly associated with FT (r = +0·44; P < 0·0001) and both were inversely related to visceral adipose tissue (VAT) (GH: r = ?0·65; P < 0·0001; FT: r = ?0·51; P < 0·0001). In multivariate regression analysis controlling for VAT, FT was no longer related to GH. Both GH and FT were associated with cIMT in univariate analysis. However, in multivariate modelling including traditional cardiovascular risk markers, GH (β = 0·003; P = 0·04) but not FT (P = 0·35) was associated with cIMT. Conclusions These results demonstrate a strong relationship between FT and GH in obesity and suggest that this relationship is more a function of excess adiposity rather than a direct relationship. While reduced FT and GH are both related to increased cIMT, the relationship with reduced GH remains significant controlling for reduced FT and traditional cardiovascular disease risk markers.     

Does partial surgical tumour removal influence the response to octreotide‐LAR in acromegalic patients previously resistant to the somatostatin analogue?

Objective To compare the intrapatient response to the same dose of slow‐release octreotide (OCT‐LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT‐LAR. Design Prospective clinical study. Patients Eleven acromegalic patients (eight men, aged 42·45 ± 11·15 years, 10 macroadenomas) received OCT‐LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT‐LAR) for 11·3 ± 4·2 months, without IGF‐I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT‐LAR for 8·0 ± 6·5 months (2ndOCT‐LAR). Measurements GH and IGF‐I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF‐I was also expressed as a percentage of the upper limit of the normal age‐ and sex‐matched range (%ULNR IGF‐I). Results After 1stOCT‐LAR, there was a decrease in GH levels (P = 0·003) and %ULNR IGF‐I (P = 0·009) compared to baseline (B), but no IGF‐I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63·7%, range 24·5–75·5%). After surgery, mean levels of GH and %ULNR IGF‐I were lower than those at baseline (P = 0·0004 and P = 0·003, respectively), but not when compared to values during 1stOCT‐LAR (P = 1·000 and P = 0·957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4·9–96·6%) in eight of the 10 patients. Comparing the 2ndOCT‐LAR results with postsurgical results, there were no significant decrease in %ULNR IGF‐I (P = 0·061) and GH levels (P = 0·414). Nine patients (82%) achieved IGF‐I normalization. The degree of surgical tumour reduction did not correlate with IGF‐I normalization (P = 0·794). When comparing the results between 1stOCT‐LAR and 2ndOCT‐LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0·059) and a significant decrease in %ULNR IGF‐I (P = 0·011). Conclusions Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT‐LAR treatment in acromegalic patients resistant to primary therapy with SA.     

Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.     

GH replacement reduces increased lipid peroxidation in GH-deficient adults

Background GH replacement improves numerous metabolic abnormalities in GH‐deficient patients; increased lipid peroxidation (LPO) has been observed in GH‐deficient patients; however, it is unknown if LPO is influenced by GH replacement. Aim and methods To evaluate the extent to which GH replacement might reverse the increased LPO in GH‐deficient adults and to analyse if this phenomenon might be involved in the improvement of metabolic disturbances due to GH treatment. Serum concentrations of malondialdehyde + 4‐hydroxyalkenals (MDA + 4‐HDA), as an index of LPO, were measured at baseline, and after 12 and 24 months of GH replacement in 40 adult patients with severe GH deficiency (both in adult‐ and childhood‐onset) and in 40 healthy volunteers, matched for sex, age and body mass index (BMI). Correlations were evaluated between LPO and lipids, IGF‐I, metalloproteinase‐2 and ‐9 (MMP‐2, ‐9), vascular endothelial growth factor (VEGF), BMI and GH dose. Results LPO values in GH‐deficient patients were several‐fold higher than in controls [55·36 ± 2·27 vs. 4·19 ± 0·42 nmol/mg protein (mean ± SEM), P < 0·0001] and decreased significantly over time with GH replacement to 38·61 ± 2·15 nmol/mg protein (i.e. by approximately 30%), though still remaining markedly elevated compared with controls (P < 0·0001). The proatherogenic lipid profile parameters correlated positively with LPO in the childhood‐onset subgroup before GH replacement. GH replacement restored the positive correlation between LPO and age in male patients (r = 0·57, P = 0·013; r = 0·8, P < 0·001, at 12 and 24 months of GH replacement, respectively). Conclusions GH replacement partially reverses the grossly abnormal LPO in GH‐deficient adults. It is highly probable, therefore, that oxidative mechanisms are involved in the overall improvement of metabolic changes due to GH replacement.     

Postnatal growth and cardiometabolic profile in young adults born large for gestational age

Context The association between large for gestational age (LGA) phenotype, postnatal growth and cardiometabolic risk (CMR) in adult life remains unclear. The role of IGF1 genotype on LGA‐related outcomes in adult life is unknown. Aim To assess the postnatal growth, IGF‐I levels, CMR and the influence of the 737.738 IGF1 in adults born LGA. Subjects Case–control study (n = 515) nested in a population‐based prospective cohort (n = 2063); 117 LGA and 398 gender‐matched controls appropriate for gestational age (AGA) subjects. Methods Anthropometry was evaluated at birth, at 9–10 and at 23–25 years old. At the age of 23–25 years, blood pressure (BP), glycaemia, insulinaemia, homeostasis model assessment – insulin resistance, lipids, fibrinogen, and plasma IGF‐I and 737.738 IGF1 polymorphism were assessed. Results Large for gestational age subjects remained heavier and taller than AGA at 9–10 and 23–25 years (P < 0·05); at 23–25 years, LGA had greater waist circumference (WC; P < 0·05) and higher BP (P < 0·05) than controls. Body proportionality at birth did not predict metabolic outcome. LGA subjects presenting catch‐down of weight in childhood had lower body mass index (BMI; P = 0·001), lower WC (P < 0·05) and lower BP (P < 0·05) at 23–25 years. 737.738 IGF‐I genotype differed between groups (P < 0·001). Homozygosis for polymorphic alleles was associated with increased odds of LGA (OR: 3·2; 95% CI: 1·5–6·9), higher IGF‐I (56·9 ± 16·4 vs 37·7 ± 16·0 nm ; P < 0·01) and lower BP (114/68 vs 121/73 mmHg; P < 0·05). Conclusions Young adults born LGA presented higher BMI, WC and BP and appear to be at higher CMR risk than AGA subjects. The 737.738 IGF1 polymorphism appears to play a role on birth size and LGA‐related metabolic outcomes.     

Reduced cardiac functional reserve and quality of life in adults with GH deficiency

Introduction Patients with severe GH deficiency (GHD) suffer with a reduced quality of life in addition to diverse changes in cardiac size and performance. So far, the cardiac reserve ability to maintain the circulation during peak exercise has not been measured. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls and that this could explain, in part, their reduced quality of life. Aims Eighteen patients with severe GHD and an assessment of GHD in adults (AGHDA) score ≥11 (mean 20·0, range 12–25) were studied and compared with 18 age‐, sex‐ and body mass index‐matched healthy controls. Peak cardiac power and cardiorespiratory fitness were investigated using noninvasive haemodynamic measurements during maximal cardiopulmonary exercise testing. Results Compared with matched controls, the cardiac power of GHD patients during exercise to volitional exhaustion was significantly reduced by 15% (mean ± SD 4·4 ± 1·0 W vs. 5·2 ± 1·0 W, P = 0·02). Patients with GHD also had lower cardiac chronotropic reserve (peak heart rate 154 ± 21/min vs. 174 ± 11/min, P = 0·001) and a lower cardiac pressure‐generating capacity (systolic blood pressure 160 ± 25 mmHg vs. 200 ± 15 mmHg, P < 0·0001). We found no correlation between any measure of peak cardiac power or function and the AGHDA score. Conclusion Using this robust noninvasive method of assessing functional cardiac pumping capacity, we have for the first time shown that, while patients with severe GHD have a significantly impaired cardiac functional reserve associated with chronotropic incompetence and impaired pressure‐generating capacity, this does not correlate with their reduced quality of life assessed using the current standard AGHDA score.