Enhancement of the peripheral sensitivity to growth hormone in adults with GH deficiency

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.     

The natural history of partial growth hormone deficiency in adults: a prospective study on the cardiovascular risk and atherosclerosis

BACKGROUND: Partial GH deficiency (GHD) in adults is poorly studied. OBJECTIVE: The objective of the study was to investigate the natural history and clinical implications of partial GHD. STUDY DESIGN: This was an analytical, observational, prospective, case-control study. PATIENTS: Twenty-seven hypopituitary patients (15 women, ages 20-60 yr) and 27 controls participated in the study. MAIN OUTCOME MEASURES: Measures included GH peak after GHRH plus arginine [(GHRH+ARG), measured by immunoradiometric assay]; IGF-I (measured after ethanol extraction) z-sd score (SDS); glucose, insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels; and common carotid arteries intima-media thickness (IMT) measured periodically. RESULTS: At study entry, partial GHD patients had significantly lower IGF-I and HDL-cholesterol levels and homeostasis model assessment index than controls. During the 60 months of median follow-up, 11 patients had severe GHD (40.7%), seven normalized their GH response (25.9%), and nine showed persistently partial GHD (33.3%). Patients with developed severe GHD at baseline had similar age and body mass index and lower GH peak (11.5 +/- 1.8 vs. 14.3 +/- 1.5 and 12.8 +/- 1.1 microg/liter, P = 0.008) and IGF-I SDS (-0.88 +/- 0.48 vs. 0.15 +/- 0.58 and -0.42 +/- 0.78; P = 0.01) than the patients with normal GH secretion or partial GHD. Severe GHD was accompanied by decreased IGF-I SDS and increased total to HDL cholesterol ratio, triglycerides, homeostasis model assessment index, and carotid intima-media thickness; normalization of GH secretion was accompanied by increased IGF-I SDS. By receiving-operator characteristic analysis, predictors of severe GHD were a baseline GH peak after GHRH+ARG of 11.5 microg/liter (sensitivity 64%, specificity 94%) and a baseline IGF-I SDS of -0.28 (sensitivity 91%, specificity 63%). CONCLUSIONS: Of 27 patients with partial GHD after pituitary surgery, 40.7% developed severe GHD and 25.9% normalized their GH response. With the assay used, changes in the GH peak response to GHRH+ARG were accompanied by changes in the IGF-I SDS, metabolic profile, and carotid IMT. A peak GH of 11.5 microg/liter or less and IGF-I SDS -0.28 or less were highly predictive of delayed deterioration of GH secretion.     

Growth hormone deficiency (GHD) in adult thalassaemic patients

BACKGROUND AND OBJECTIVE: Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin-like growth factor-I (GH-IGF-I) axis in a large group of adult thalassaemic subjects. DESIGN: Cross-sectional study on the prevalence of GHD in 94 adult thalassaemic patients (69 with thalassaemia major and 25 with thalassaemia intermedia, 39 men and 55 women, aged 31.5 +/- 6.8 years, on sex steroid replacement when necessary). METHODS: All patients underwent GHRH (1 microg/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 lower than 9 microg/l, whereas partial GHD was defined by GH peaks ranging from 9-16.5 microg/l. Blood samples for IGF-I, ferritin and pseudocholinesterase measurements were collected. Urinary free cortisol (UFC) levels were also assayed. RESULTS: Severe GHD was demonstrated in 21 of the 94 patients (22.3%), while 18 additional patients (19.1%) displayed partial GHD. GH peaks were positively correlated with IGF-I standard deviation score (SDS) (r = 0.22, P < 0.05), although 1 of the 21 patients with severe GHD showed normal IGF-I SDS values, and 44 of the 55 patients with normal GH reserve displayed low IGF-I SDS. A strong positive correlation (r = 0.48, P < 0.0001) between IGF-I SDS and pseudocholinesterase was identified. No correlations were found between ferritin and UFC levels on the one hand and GH peaks and IGF-I SDS on the other. CONCLUSION: Findings from this study demonstrate that GHD, either partial or severe, is not a rare occurrence in adult thalassaemic patients. GHD is associated with a higher prevalence of low serum IGF-I levels, recorded also in patients with normal GH secretion. The lack of correlation between ferritin and both GH peaks and IGF-I SDS suggests that mechanisms additional to iron overload, whose relevance cannot however be definitely ruled out, play a role in the pathophysiology of somatotrophin-somatomedin deficiency in this clinical condition. The positive correlation between IGF-I SDS on the one hand and GH peaks and pseudocholinesterase values on the other hand indicates that reduced liver protidosynthetic activity, in addition to somatotrophin secretory status, is a major determinant of the impaired IGF-I production in thalassaemia. Therefore biosynthetic GH replacement therapy in GH-deficient thalassaemic adults is worth considering.     

Growth hormone releasing hormone plus arginine stimulation testing in young adults treated in childhood with cranio-spinal radiation therapy

OBJECTIVE: Growth hormone deficiency (GHD) secondary to cranio-spinal radiation therapy (CSRT) is a complication seen in medulloblastoma survivors. The standard for diagnosis of adult GHD is a peak GH < 3 microg/l by the insulin tolerance test (ITT). However, insulin tolerance testing exposes patients to the risks of hypoglycaemia. Recent studies suggest that the GH releasing hormone + arginine (GHRH + ARG) test can identify GHD in cranially irradiated patients at longer time intervals after radiation. We evaluated the GHRH + ARG stimulation test compared to the ITT in young adults diagnosed with medulloblastoma during childhood. PATIENTS: We evaluated 10 young adult patients (age range 17-26 years) who were treated with CSRT during childhood for medulloblastoma, and who had resultant childhood-onset GHD. MEASUREMENTS: Subjects underwent GH provocative testing with the ITT and the GHRH + ARG test. IGF-I and IGFBP3 levels were also measured at baseline. RESULTS: Insulin tolerance testing and GHRH + arginine stimulation were performed at a mean +/- SD 14 +/- 4.4 years after cranial radiation. All patients failed the ITT with median peak GH 0.40 microg/l (range < 0.05-2.2). GHRH + arginine gave higher peak GH levels with a mean of 7.9 +/- 5.7 microg/l (P = 0.003). Four patients had peak GH > 9 microg/l and were between 7.8 and 19.6 years from cranial radiation. There was no correlation of peak GH levels with time interval since CSRT. Thirty-three per cent of subjects had normal IGF-I; neither IGF-I nor IGFBP3 standard deviation scores (SDS) correlated with ITT results. CONCLUSIONS: Using a GHRH + arginine cut-off for GHD of 9 microg/l, four patients would have been misclassified as GH sufficient, despite being > 7 years (with two patients being nearly 20 years) out from CSRT. These findings suggest that the pituitary GH-producing cells of young adults continue to maintain responsiveness to GHRH + arginine more than 5-10 years after cranial irradiation.     

Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults

OBJECTIVE: To evaluate circulating levels of ghrelin and adiponectin (ApN) in GH-deficient (GHD) adults before and after short- and long-term recombinant human GH (rhGH) administration. PATIENTS AND METHODS: Twenty-three patients were studied. Seventeen subjects (Group A, 12 men, five women) were evaluated at baseline and after 1 year rhGH therapy (dose mean +/- SD: 0.3 +/- 0.1 mg/day) with the assessment of serum IGF-I, ghrelin, ApN, leptin, insulin and glucose levels, percentage of body fat (BF%), HOMA-IR and QUICKI. Seventeen age-, sex- and body mass index (BMI)-matched healthy subjects were recruited for comparisons. Six patients (Group B, three men, three women) underwent IGF-I generation test (rhGH 0.025 mg/kg/day for 7 days), blood sampled at baseline and on day 8 for determination of IGF-I, ghrelin and ApN levels. RESULTS: Group A: at baseline GHD patients showed low IGF-I levels and BF% significantly higher than controls (31.4 +/- 2.5 vs. 26.4 +/- 1.3, P < 0.05). Glucose, insulin, leptin, tryglicerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as HOMA-IR and QUICKI values were similar in the two series, while total cholesterol levels were higher in GHD. In GHD, ghrelin levels were significantly lower than in controls (193.9 +/- 27.1 vs. 298.1 +/- 32.5 pmol/l, respectively, P = 0.02), while ApN levels were similar (10.2 +/- 1.1 and 9 +/- 1 mg/l, respectively, P = ns). After 1 year of rhGH therapy, BF%, BMI, serum total and LDL cholesterol significantly decreased, serum leptin levels showed a trend to decrease, while HOMA-IR and QUICKI did not change. Ghrelin and ApN levels significantly increased from 193.9 +/- 27.1 to 232.4 +/- 26.3 pmol/l (P < 0.01) and from 8.6 +/- 0.8 to 10.3 +/- 1.1 mg/l (P < 0.05), respectively. In group B, the expected increase in IGF-I levels was associated with a significant decrease in ghrelin levels, while ApN did not change. CONCLUSION: GHD patients showed serum ghrelin lower than controls, probably due to the higher BF%. No difference in ApN was observed. Ghrelin and ApN increments induced by long-term treatment may be related to the significant BMI and BF% reduction that is the predominant metabolic effect of rhGH therapy. Conversely, the decrease in ghrelin levels observed after short-term rhGH administration may be consistent with an inhibitory feedback of GH and/or IGF-I on ghrelin release.     

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.     

Exercise training benefits growth hormone (GH)-deficient adults in the absence or presence of GH treatment

Reduced aerobic capacity is a prominent manifestation among patients with GH deficiency (GHD). Exercise training may improve the physiological capacity to undertake aerobic activity. The ability of patients with GHD to participate in and benefit from a structured program of aerobic exercise with or without replacement recombinant human GH (rhGH) was investigated. We examined the effect of aerobic training on cycle ergometers in a double-blind crossover trial. Ten patients with GHD trained for 3 months with rhGH (6 microg/kg.d) or placebo, stopped both exercise and drug for 2 months, and resumed training for another 3 months with the other agent. Peak oxygen uptake (VO(2)peak) and ventilation threshold (VeT) were measured during a progressive cycle ergometer test to fatigue or symptom-limited maximum. Serum IGF-I levels were monitored to assess compliance with GH treatment. VO(2)peak was low at the two baseline measures (B1, 19.3 +/- 5.5; B2, 19.9 +/- 6.9 ml/kg.min; normal, approximately 30 ml/kg.min) as was VeT (B1, 11.6 +/- 2.2 ml/kg.min; B2, 11.7 +/- 2.6 ml/kg.min; normal, approximately 16 ml/kg.min). Exercise training increased VeT with (8.6%) or without (9.4%) rhGH treatment. Similarly, exercise training resulted in significant reduction in submaximal heart rate in the presence (-5 +/- 4 beats per minute; P < 0.05) or absence of rhGH treatment (-4 +/- 4 beats per minute; P < 0.05). Peak oxygen uptake was not significantly affected by training with or without rhGH treatment. Our findings suggest that exercise training is a feasible intervention in GH-deficient adults that can measurably improve their submaximal responses to exercise. The beneficial effects of exercise can mimic and are not additive to the effects of GH treatment alone.     

TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy.

OBJECTIVE: Growth hormone (GH) has been suggested to modulate the release of some cytokines including TNF-alpha. To investigate TNF-alpha levels in children with GH deficiency (GHD), to evaluate alteration in TNF-alpha levels during recombinant human GH (rhGH) treatment, and to analyze possible correlations between TNF-alpha and GH, IGF-1 and IGFBP-3. DESIGN: Twenty-four children, aged 12.60+/-2.27 years, with isolated GHD and given rhGH therapy, as subcutaneous ingestion of 0.03-0.04mg/kg once-daily dose, were evaluated. Eleven had complete and 13 had partial GHD. Thirty-three healthy children were studied as controls. Age and sex distribution, body mass indexes of two groups were similar. In children with GHD, blood samples were drawn before (TNF-alpha0), and at 6 (TNF-alpha6) and 12 (TNF-alpha12) months of the treatment with rhGH. TNF-alpha was determined using a human TNF-alpha ELISA assay (Biosource International). RESULTS: TNF-alpha0 levels were significantly higher in children with GHD than in controls (41.79+/-25.04 and 8.63+/-4.48pg/ml, respectively, p<0.001) and decreased significantly during rhGH treatment (TNF-alpha0=41.79+/-25.04, TNF-alpha6=13.67+/-9.95, TNF-alpha12=10.86+/-6.61pg/ml, p<0.05). There was no correlation between TNF-alpha levels and BMI, IGF-1/logIGF1, IGFBP-3 levels and growth velocity of the patients with GHD. Although no correlation between TNF-alpha and peak GH levels after stimulation was present; a moderate reverse correlation between TNF-alpha and basal serum concentrations of GH (r=-0.512, p=0.046) was demonstrated. CONCLUSIONS: TNF-alpha levels are significantly higher in children with GHD than the controls, and long-term therapy with rhGH effectively reduces its level. Our data suggest that GH plays an inhibitory role on TNF-alpha release in humans. However, due to inconsistent results up to now, further prospective, controlled and long term studies are needed to elucidate the issue.     

Recombinant hGH replacement therapy and the hypothalamus–pituitary–thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?

OBJECTIVE: Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD. DESIGN: Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. MEASUREMENT AND STUDY SUBJECTS: Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study. RESULTS: Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels (P < 0.01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups. CONCLUSION: Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD.     

Increased orderliness of growth hormone (GH) secretion in GH-deficient adults with low serum insulin-like growth factor I

Available studies suggest that a proportion of GH-deficient (GHD) adults maintain serum IGF-I concentrations within the age- and sex-matched normal range. The basis for this distinction is not known. In this study 24-h GH profiles (sampling every 30 min) were appraised in five GHD adults with low serum IGF-I concentrations (<2 SD of the age- and sex-matched normal range), five GHD adults with normal serum IGF-I levels (within +/-2 SD), and five healthy subjects. Serial GH concentrations, measured using a chemiluminescence assay, were analyzed by deconvolution and approximate entropy (ApEn; regularity) analyses. The apparent half-duration of GH secretory bursts was longer in both GHD groups than in the healthy controls, as determined by deconvolution analysis (P < 0.05 each). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in GHD adults with normal serum IGF-I than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The percentage of total daily GH secretion that was pulsatile was also reduced in the GHD adults with normal serum IGF-I compared with the other two groups (P < 0.05 and P < 0.05, respectively). In contrast, ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I and controls (P < 0.01 and P < 0.05, respectively). Serum IGF-I concentrations correlated positively with ApEn ratios in the total study population (n = 15) and in the GHD adults (n = 10). In conclusion, 24-h patterns of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. GHD adults with low IGF-I levels maintain low ApEn ratios (denoting greater relative orderliness of GH secretion), whereas GHD patients with normal IGF-I values generate a high frequency, low amplitude GH output. The foregoing contrasts point to distinct neuroendocrine features of the GH-deficient state of adults, which can be related to concurrent IGF-I production.     

Relationship between the morphological evaluation of the pituitary and the growth hormone (GH) response to GH-releasing hormone Plus arginine in children and adults with congenital hypopituitarism

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.     

Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement

OBJECTIVE: This open, prospective study was designed to evaluate the effect of growth hormone deficiency (GHD) and GH replacement therapy on serum homocysteine (Hcy) concentration in children with GHD. SUBJECTS: Seventeen prepubertal children with GHD (11 boys and six girls) aged 8.6 +/- 1.9 years were studied before and after 12 months of GH replacement therapy at a dose of GH of 30 microg/kg/day. Seventeen healthy children acted as controls and were matched for age, sex and body mass index (BMI). METHODS: At study entry, height, weight, blood pressure, serum Hcy, serum IGF-I, total-low density lipoprotein (LDL)- and high density lipoprotein (HDL) cholesterol, triglycerides, free T4, free T3, vitamin B12, folate, glucose and creatinine were measured in all subjects. The atherogenic index (AI) was also calculated as the ratio of total cholesterol/HDL cholesterol (T/HDL). In GHD children these parameters were also revaluated after 12 months of GH therapy. RESULTS: At study entry height and serum IGF-I were significantly lower, as expected, in GHD patients than in controls (P < 0.0001 and P < 0.007, respectively). Serum Hcy levels were significantly higher in GHD patients than in healthy children (8.4 +/- 2.9 vs. 6.0 +/- 2.9 micromol/l; P < 0.03), although the absolute values were within the normal values for age and sex. There were no significant differences at baseline with respect to blood pressure, serum vitamin B12, folate, fT3, fT4, lipid profile, creatinine and glucose levels. After 12 months of GH replacement therapy height and serum IGF-I increased significantly compared to pretreatment values (P < 0.0001); serum Hcy levels decreased significantly (6.0 +/- 3.3 micromol/l; P < 0.002) compared to baseline values, becoming similar to control values. Total cholesterol (3.5 +/- 0.6 mmol/l) and the AI (2.5 +/- 0.8) decreased significantly with respect to both pretreatment (4.2 +/- 1.0 mmol/l; P < 0.0002 and 3.4 +/- 0.8; < 0.002, respectively) and control values (4.2 +/- 0.4 mmol/l; P < 0.0005 and 3.3 +/- 1.1; P = 0.02, respectively). CONCLUSIONS: GHD in children is associated with higher serum levels of Hcy compared to controls, without significantly affecting the lipid profile. GH replacement for 12 months significantly decreased the Hcy levels and improved the lipid profile with a decrease of total cholesterol and the total/HDL cholesterol ratio, compared to pretreatment values. Given the small number of patients, further larger studies are needed to clarify whether these results may have significant effects in the prevention of cardiovascular disease in adulthood.     

Sustained effects of recombinant GH replacement after 7 years of treatment in adults with GH deficiency

CONTEXT: The goal of GH replacement with recombinant human GH (rhGH) is to ameliorate symptoms, signs, and complications of adult GH deficiency (GHD) in the long term. To determine whether the observed short-term beneficial effects of rhGH treatment are sustained in the long term, we evaluated biochemical and anthropometric parameters after 7 years of rhGH replacement. PATIENTS AND METHODS: After 2, 5, and 7 years of rhGH replacement, 63 adult GHD patients (30 men, 52 adult-onset GHD) were assessed. IGF-I increased during rhGH replacement, and a stable dose of rhGH was reached within 1 year of rhGH substitution. Thereafter, this individualized dose was continued. RESULTS: Plasma levels of total cholesterol and low-density lipoprotein cholesterol decreased even after 5 years of rhGH replacement (11% decrease, P < 0.001; 22% decrease, P < 0.001 respectively). High-density lipoprotein cholesterol levels increased during 7 years of rhGH replacement (1.4 +/- 0.5 mmol/l at baseline vs 1.7 +/- 0.5 mmol/l after 7 years, P < 0.001), whereas triglyceride concentrations remained unchanged. Fasting glucose levels increased during follow-up, mainly during the first 2 years of rhGH replacement (4.4 +/- 0.7 mmol/l to 5.0 +/- 1.0 mmol/l, P < 0.001). Body mass index increased during follow-up, whereas waist circumference and waist-to-hip ratio remained unchanged. Diastolic blood pressure decreased (P = 0.002), but when patients using antihypertensive medication were excluded this decrease did not reach significance (P = 0.064). Systolic blood pressure remained unchanged. CONCLUSION: The beneficial effects of rhGH replacement, described after short-term rhGH replacement, are sustained in the long term up to 7 years.     

Serum IGF-I and IGFBP-3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours

OBJECTIVE: The growth hormone (GH)-dependent growth factors insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF-I or IGFBP-3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI). DESIGN: Retrospective case review of all patients followed at our centre with GHD following treatment of BT. PATIENTS: 72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre-GH treatment IGF-I and IGFBP-3 levels were obtained. MEASUREMENTS: Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre-GH treatment serum IGF-I and IGFBP-3 concentrations. RESULTS: IGF-I levels were normal (above -2 SD) in 19 of 70 children (27%), and IGFBP-3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF-I (r = 0.328, p < 0.006) and IGFBP-3 (r = 0.364, P < 0.02). Normal IGF-1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0. 05). IGFBP-3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels. CONCLUSIONS: Low IGF-I levels were more predictive of growth hormone deficiency than low IGFBP-3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic-chiasmatic glioma and in pubertal children. Serum IGF-I and IGFBP-3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic-chiasmatic glioma or those already in puberty.     

Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic-pituitary-adrenal axis in children with idiopathic isolated GH deficiency

Objective Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11β‐hydroxysteroid dehydrogenase type 1 isoenzyme (11βHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic–pituitary–adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. Design and patients This was a single‐centre study of 10 consecutive children [five males and five females, mean age: 12·2 ± 1·0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10·9 ± 2·9 months, mean dose: 0·030 ± 0·002 mg/kg bw/day). Measurements HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 µg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. Results On rhGH therapy, serum IGF‐I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 ± 41 vs. 580 ± 35 nmol/l, respectively, P = 0·06), the mean cortisol rise being 280 ± 45 and 270 ± 36 nmol/l on rhGH and at baseline, respectively. Conclusions According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.     

The effects of recombinant human growth hormone (rhGH) supplementation on adipokines and C-reactive protein in obese subjects.

OBJECTIVE: Obese subjects have functional growth hormone deficiency (GHD). Recombinant human GH (rhGH) treatment of pituitary GHD improves serum levels of leptin, adiponectin and C-reactive protein (CRP). This study was undertaken to determine whether these rhGH-induced changes occur in obese subjects during rhGH supplementation. DESIGN: Randomized double-blind placebo-controlled trial of low-dose rhGH (200 microg/day for the first month, then 400 microg/day for men and 600 microg/day for women thereafter) or placebo supplementation as an adjuvant to a standard weight loss program. SUBJECTS: Forty healthy obese subjects, 28 premenopausal menstruating women (35+/-7 SD years) and 12 men (37+/-6 years). MEASUREMENTS: Body weight, BMI, body composition (assessed by dual energy X-ray absorptiometry [DEXA]), and serum levels of glucose, insulin, IGF-I, IGFBP-3, insulin resistance index (homeostasis modal assessment [HOMA]), leptin, CRP and adiponectin were performed at baseline and at 6 months. RESULTS: For similar entry BMI values, women when compared with men had higher percent body fat (BF) (43.5+/-4.6% vs. 29.8+/-4.0%, p<0.001), higher leptin levels (16.9+/-8.4 microg/L vs. 4.2+/-3.0 microg/L, p<0.001), and higher CRP levels (13.8+/-16.8 mg/L vs. 2.4+/-3.2mg/L, p=0.04). Serum levels of leptin and CRP, but not adiponectin, correlated significantly with BF in both sexes. Recombinant human GH treatment increased levels of IGF-I Z-Score between baseline and 6 months (from -0.7+/-0.9 SD to 0.1+/-1.1 SD, p=0.01) and modestly decreased BF (from 38.4+/-7.8% to 35.6+/-7.5%, p=0.046). Despite increased IGF-I, there were no differences between rhGH and placebo with regard to changes in leptin, CRP, or adiponectin. CONCLUSION: It is concluded that in obesity, although rhGH treatment significantly increases IGF-I and modestly reduces body fat, the lack of significant changes in serum leptin, adiponectin or CRP levels suggests that rhGH treatment does not have a significant effect on these serum markers of adiposity.     

Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy.

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.     

Short children with familial short stature show enhancement of somatotroph secretion but normal IGF-I levels

The aim of the present study was to evaluate the GH status in children with familial, idiopathic short stature (FSS). To this goal we evaluated the GH response to GHRH (1 microg/kg iv) + arginine (ARG) (0.5 g/kg iv) test which is one of the most potent and reproducible provocative tests of somatotroph secretion, in 67 children with FSS [50 boys and 17 girls, age 10.8+/-0.4 yr, pubertal stages I-III, height between -3.6 and -1.6 standard deviation score (SDS), target height <10 degrees centile, normality of both spontaneous and stimulated GH secretion as well as of IGF-I levels]. The results in FSS were compared with those in groups of children of normal height (NHC) (42 NHC, 35 boys and 7 girls, age 12.0+/-0.5 yr, pubertal stages I-III, height between -1.3 and 1.4 SDS, height velocity standard deviation score (HVSDS)>25 degrees centile, GH peak >20 microg/l after GHRH+ARG test, mean GH concentration [mGHc]>3 microg/l) and children with organic GH deficiency (GHD) (38 GHD, 29 boys and 9 girls, age 11.2+/-3.7 yr, pubertal stages I-III, height between -5.7 and -1.3 SDS, GH peak <20 microg/l after GHRH +ARG test, mGHc <3 mg/l). Basal IGF-I levels and mGHc were also evaluated in each group over 8 nocturnal hours. IGF-I levels in FSS (209.2+/-15.6 microg/l) were similar to those in NHC (237.2+/-17.2 microg/l) and both were higher (p<0.0001) than those in GHD (72.0+/-4.0 microg/l). The GH response to GHRH +ARG test in FSS (peak: 66.4+/-5.6 microg/l) was very marked and higher (p<0.01) than that in NHC (53.3+/-4.5 microg/l) which, in turn, was higher (p<0.01) than in GHD (8.2+/-0.8 microg/l). Similarly, the mGHc in FSS was higher than in NHC (6.7+/-0.5 microg/l vs 5.1+/-0.7 microg/l, p<0.05) which, in turn, was higher than in GHD (1.5+/-0.2 microg/l, p<0.0001). In conclusion, our present study demonstrates that short children with FSS show enhancement of both basal and stimulated GH secretion but normal IGF-I levels. These findings suggest that increased somatotroph function would be devoted to maintain normal IGF-I levels thus reflecting a slight impairment of peripheral GH sensitivity in FSS.     

A rare case of adulthood-onset growth hormone deficiency presenting as sporadic, symptomatic hypoglycemia

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.     

Deterioration of growth hormone (GH) response and anterior pituitary function in young adults with childhood-onset GH deficiency and ectopic posterior pituitary: a two-year prospective follow-up study

CONTEXT: The current criteria for definition of partial GHD in young adults are still a subject of debate. OBJECTIVES: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion. DESIGN AND SETTING: This was a prospective explorative study conducted in a university research hospital. PATIENTS AND METHODS: Thirteen subjects with a mean age of 17.2 +/- 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 microg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up. RESULTS: At mean age of 19.2 +/- 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 microg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004). CONCLUSIONS: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.