Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis.

CONTEXT: GH replacement in adult GH-deficient patients may cause insulin resistance, raising concerns of potential increased risk of developing diabetes mellitus (DM). OBJECTIVE: Our objective was to assess DM prevalence and incidence in the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database. DESIGN AND PARTICIPANTS: GH-treated patients enrolled into HypoCCS (2922 U.S. and 3709 European patients) were assessed for DM, defined as recorded on the clinical report form, reported as adverse events, fasting glucose at least 7 mmol/liter recorded at least twice, or insulin treatment reported. RESULTS: DM prevalence was 8.2% [95% confidence interval (CI) = 7.6-8.9] overall, 11.3% in the United States and 5.7% in Europe. Incidence (n/1000 patient-years) was 9.7 (95% CI = 8.4-10.9) overall, 14.1 (11.5-16.7) in the United States, and 7.0 (5.6-8.3) in Europe. Overall incidence was 2.1 (0.9-3.3) for patients with body mass index (BMI) below 25 kg/m(2) increasing to 16.4 (13.7-19.1) for BMI over 30 kg/m(2). Obesity (BMI > 30 kg/m(2)) prevalence was higher in the United States than Europe and higher in U.S. patients than a U.S. reference population. After age, gender, and BMI adjustment, U.S. HypoCCS DM incidence was 10.6 (8.1-13.0), compared with 7.1 (6.0-8.1) in the National Health Interview Survey. In Europe, incidence for French and German patients was comparable to reference populations; for Sweden, the point estimate was higher than the reference population, but 95% CI overlapped. GH dose was not correlated with DM incidence. CONCLUSIONS: The present analysis showed no evidence for increased DM incidence in GH-treated adult hypopituitary patients. However, those more prone to develop DM exhibited a higher than normal prevalence of obesity.

Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement.

CONTEXT AND OBJECTIVE: Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). PATIENTS: We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. RESULTS: Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m(2) or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 microg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). CONCLUSION: MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment.

Changing patterns of the adult growth hormone deficiency diagnosis documented in a decade-long global surveillance database.

BACKGROUND: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996. METHODS: Baseline demographics, reported cause of GHD, and diagnostic tests were available from 5893 GH-treated patients. Trends for change over time in diagnosis, GH stimulation test data, and IGF-I measurements were analyzed at 2-yr intervals by linear regression models, with entry year as the predictive variable. RESULTS: Over the decade, there was a decrease in patients enrolled with diagnoses of pituitary adenoma (50.2 to 38.6%; P < 0.001), craniopharyngioma (13.3 to 8.4%; P = 0.005) and pituitary hemorrhage (5.8 to 2.8%; P = 0.001); increases in idiopathic GHD (13.9 to 19.3%; P < 0.001), less common diagnoses (7.4 to 15.8%; P < 0.001), and undefined/unknown diagnoses (1.3 to 8.6%; P < 0.001) were observed. Use of arginine, clonidine, and L-dopa tests declined, whereas use of the GHRH-arginine test increased. Median values for peak GH from all tests except GHRH-arginine and for IGF-I SD scores increased significantly (P < 0.001). Over the decade (1996--2005), idiopathic GHD was reported for 16.7% of patients, and more than half of these had adult onset GHD. In the idiopathic adult onset group, 40.2% had isolated GHD; 18.3 and 4.4% had a stimulation test GH peak of at least 3.0 and 5.0 microg/liter, respectively. CONCLUSIONS: Significant shifts in diagnostic patterns have occurred since approval of the adult GHD indication, with a trend to less severe forms of GHD.

Growth hormone and the transition from puberty into adulthood.

With modern growth hormone (GH) replacement algorithms, children with a diagnosis of growth hormone deficiency achieve at the end of pediatric GH treatment an adult height that is on the average in the normal range. Recent experience with GH replacement in young adults with childhood-onset growth hormone deficiency, however, has shown that these patients present with variable degrees of somatic immaturity. As childhood GH treatment is discontinued when final height is attained, attention moves to the phase of somatic development that follows the end of longitudinal growth, called ''transition'', which had been excluded previously from consideration for either pediatric or adult GH replacement. This article reviews the changes taking place during this phase of development and their relevance for the attainment of adult body maturation. The critical role of GH in this process is described.

An individualized GH dose regimen for long-term GH treatment in Japanese patients with adult GH deficiency.

OBJECTIVES: To investigate the effects of growth hormone (GH) treatment, using a dose-adjustment regimen based on serum insulin-like growth factor (IGF)-I concentrations, in adult Japanese hypopituitary patients with GH deficiency. STUDY DESIGN: Japanese patients who had initially been administered GH (n = 31) or placebo (n = 28) in a 24-week double-blind study received individualized GH treatment in an open-label study for 48 weeks. Body composition from dual-energy X-ray absorptiometry (DXA) and serum IGF-I, IGF-binding protein 3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: Significant increases in lean body mass (4.5%) and decreases in fat mass (-10.5%) were observed in the group that received individualized GH doses in the present open-label study following placebo in the double-blind study. This was comparable with the changes observed in these parameters (4.7 and -9.2%, respectively) with fixed-dose GH treatment in the double-blind study; this latter group maintained these improvements throughout the open-label study. Individualized dose adjustment allowed for more moderate dose increases than the fixed-dose titration method. Individualized dosing also resulted in a lower mean dose for adult-onset compared with childhood-onset GH-deficient patients (0.032+/-0.019 versus 0.061+/-0.023 mg/kg per week for patients treated with GH for 48 weeks in the open-label study following placebo in the double-blind study). Dosing patterns in the two groups were paralleled by the changes in IGF-I and IGFBP-3. The incidence of oedema and cases with high IGF-I level were less frequent under the IGF-I controlled regimen compared with those during the fixed-dose titration method. CONCLUSION: Individualized GH administration based on IGF-I levels was safe and effective. This regimen demonstrated differences in dose requirements between adult- and childhood-onset patients. An individualized dose regimen is recommended in adult Japanese GH-deficient patients.

Quality of life in childhood onset growth hormone-deficient patients in the transition phase from childhood to adulthood.

BACKGROUND: Quality of life (QoL) has not been specifically assessed in GH-deficient (GHD) transition patients. METHODS: We assessed QoL at baseline and after 1 and 2 yr of GH treatment in severely GHD patients, using an adult GHD-specific questionnaire, QLS(M)-H. Subjects were randomized to GH, 25.0 microg/kg.d (n = 25) or 12.5 microg/kg.d (n = 28), or no treatment (n = 13). sd scores for QLS-H were calculated from normative data, specific to country of origin, gender, and age range of the patients. RESULTS: Baseline QLS-H sd scores were -0.35 +/- 1.17 in females and -0.70 +/- 1.05 in males (P = 0.280). sd scores for individual dimensions of ability to become sexually aroused, ability to tolerate stress, body shape, concentration, initiative/drive, physical stamina, and self-confidence were significantly lower than the normal average. Particularly affected were body shape (sd score, -0.80 +/- 0.99; quartile (Q)1:Q3, -1.52:-0.29) and sexual arousal (sd score, -0.41 +/- 0.88; Q1:Q3, -1.15:-0.13). Total QLS-H sd score increased slightly but not significantly for combined GH treatment groups compared with control at yr 1 (0.047 +/- 1.51 vs. -0.32 +/- 1.66; P = 0.845) but not after yr 2 (-0.00 +/- 0.80 vs. 0.12 +/- 0.89; P = 0.385); no dose effect of GH was observed. GH treatment significantly increased sd score from baseline to yr 2 for sexual arousal and body shape (0.23 +/- 0.78, P = 0.038; and 0.46 +/- 1.26, P = 0.035, respectively). CONCLUSION: Although overall baseline QoL was not compromised in severely GHD patients during the transition period, dimensions related to age-specific psychological problems were significantly worse than healthy subjects and appeared to positively respond to GH treatment.

Growth hormone (GH) treatment to final height in children with idiopathic short stature: evidence for a dose effect.

OBJECTIVES: To investigate in an open-label randomized study, the effect of two doses of growth hormone (GH) on final height and height velocity during the first 2 years of treatment of children with idiopathic short stature (mean baseline height standard deviation score [SDS] -3.2). STUDY DESIGN: Patients were treated with GH at 0.24 mg/kg/week, 0.24 mg/kg/week for the first year and at 0.37 mg/kg/week thereafter (0.24-->0.37), or 0.37 mg/kg/week. Final height was evaluated in 50 patients at study completion (mean treatment duration, 6.5 years). RESULTS: Patients who received 0.37 mg/kg/week (n = 72) experienced a significantly greater increase in height velocity than those who received 0.24 mg/kg/week (n = 70) (treatment difference = 0.8 cm/year; P = .003) or 0.24-->0.37 mg/kg/week (n = 67) (treatment difference = 0.9 cm/year; P = .001). For the 50 patients for whom final height measurements were available, mean height SDS increased by 1.55, 1.52, and 1.85 SDS, respectively, for the three dose groups. For the primary comparison between the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, the mean treatment difference (adjusted for differences in baseline predicted height SDS) was 0.57 SDS (3.6 cm; P = .025). Mean overall height gains (final height minus baseline predicted height) were 7.2 cm and 5.4 cm for the 0.37 mg/kg/week and 0.24 mg/kg/week dose groups, respectively, without dose effects on safety parameters. Final height measurements were within the normal adult height range for 94% of patients randomized to 0.37 mg/kg/week who continued to final height. CONCLUSION: GH treatment dose-dependently increases height velocity and final height in children with idiopathic short stature.

Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.

Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 microg/kg x d (pediatric dose; n = 58) or 12.5 microg/kg x d (adult dose; n = 59) or no GH treatment (control; n = 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGF-binding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 +/- 11.7%) was not different from that seen with the lower adult dose (12.7 +/- 9.4%; P = 0.970). Similarly, the decrease in FM was significantly (P = 0.029) influenced by treatment, but with no dose effect (adult dose, -7.1 +/- 22.8%; pediatric dose, -6.0 +/- 26.6%; P = 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 +/- 9.8% and 14.3 +/- 11.7% LBM (P = 0.711) and lost 12.4 +/- 22.2% and 11.0 +/- 27.1% FM (P = 0.921) with the low and high doses, respectively. Females gained 8.3 +/- 7.3% and 12.5 +/- 12.8% LBM with the two doses (P = 0.630), but increased their FM by 3.5 +/- 16.2% with the lower dose and lost only 1.2 +/- 23.2% FM with the higher dose (P = 0.325). A similar pattern was seen in IGF-I sd score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P = 0.008), but not males (P = 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males.

Adult GH deficiency in Japanese patients: effects of GH treatment in a randomised, placebo-controlled trial.

OBJECTIVE: To evaluate the influence of factors intrinsic to the Japanese population on consequences of growth hormone deficiency (GHD) and effects of GH treatment in adult Japanese hypopituitary patients with GHD. STUDY DESIGN: A 24-week, randomised, placebo-controlled, double-blind study in 64 patients in Japan, with GHD onset during adulthood (AO; n=27) or childhood (CO; n=37). Body composition measured by dual-energy X-ray absorptiometry (DXA) was evaluated centrally. Serum IGF-I, IGF binding protein-3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: In contrast to Caucasian patients, there were no significant differences before treatment between AO and CO patients for body mass index (BMI), lean body mass (LBM) and fat mass (FM). Baseline BMI was >/=25 kg/m(2) for 32.8% of patients. For all patients combined, a significant increase in LBM and decrease in FM (P<0.001 for each) was seen with GH treatment. Serum IGF-I and IGFBP-3 were significantly lower at baseline in CO compared with AO patients, similar to Caucasian patients, and were increased in both onsets following GH treatment. Serum total and low-density lipoprotein (LDL)-cholesterol concentrations did not differ between AO and CO patients at baseline and were elevated compared with normal ranges. GH-induced decreases were significant compared with placebo for both total (P=0.036) and LDL-cholesterol (P=0.040). Glycosylated haemoglobin was increased with GH compared with placebo treatment (P=0.016) but remained within the upper limit of normal for all patients at endpoint. CONCLUSIONS: Adult Japanese hypopituitary patients with GHD demonstrated obesity relative to healthy Japanese subjects but the clinical presentation differed from that of Caucasian patients. GH treatment improved body composition and serum cholesterol profiles of adult Japanese hypopituitary patients with GHD.

Long-term improvement of quality of life during growth hormone (GH) replacement therapy in adults with GH deficiency, as measured by questions on life satisfaction-hypopituitarism (QLS-H).

Questions on Life Satisfaction-Hypopituitarism (QLS-H) is a new quality-of-life (QoL) questionnaire developed for adults with hypopituitarism. To determine the effects of long-term GH treatment on QoL, we evaluated QLS-H Z-scores in 576 adult patients with GH deficiency (GHD) enrolled in HypoCCS, an international observational study, using data from five countries in which comparative QLS-H data from the general population were available. Baseline QLS-H Z-scores were significantly lower in GH-deficient patients than in the general population of the same age, gender, and nationality. Z-scores were also significantly lower in female patients vs. males (P = 0.006) and in adult-onset vs. childhood-onset GHD (P = 0.002). Multivariate analysis associated female gender, multiple pituitary hormone deficiencies, low serum IGF-I values (<75 micro g/liter), and concomitant antidepressant medication with low baseline Z-scores. QLS-H Z-scores increased from -1.02 +/- 1.43 (SD) at baseline to -0.25 +/- 1.34 (SD) after 1 yr of GH treatment (P < 0.001) and were no longer significantly different from the general population after 4 yr of treatment. There was no correlation between change in Z-score and GH dose or changes in IGF-I and IGF binding protein-3 during treatment. This study demonstrates that 1) improvements in QoL, as measured by the QLS-H, are maintained during long-term GH replacement therapy of adults with GHD, and 2) the QLS-H is a useful tool for evaluating QoL in hypopituitary patients treated in clinical practice. The authors suggest that evaluation of QoL should be a part of the routine clinical management of adult GH-deficient patients, complementing the measurement of surrogate biological markers or other clinical end points.

Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: a 2-year randomized, controlled, dose-ranging study.

GH treatment in children with GH deficiency is frequently terminated at final height. However, in healthy individuals bone mass continues to accrue until peak bone mass is achieved. Because no prospective data specifically prove the role of GH in attainment of peak bone mass, we performed a multinational, controlled, 2-yr study in patients who had terminated pediatric GH at final height. Patients were randomized to: GH at 25.0 microg/kg x day (pediatric dose, n = 58) or 12.5 microg/kg x day (adult dose, n = 59), or no GH treatment (control, n = 32). Bone mineral content (BMC) and density were measured by dual-energy x-ray absorptiometry and evaluated centrally. Laboratory measurements were also performed centrally. After 2 yr, significant increases were seen with both GH treatments, compared with control in bone-specific alkaline phosphatase (P = 0.004) and type I collagen C-terminal telopeptide:creatinine ratio (P < 0.001), but there were no significant dose effects. Total BMC increased by 9.5 +/- 8.4% in the adult dose group, 8.1 +/- 7.6% in the pediatric dose group, and 5.6 +/- 8.4% in controls (analysis of covariance, P = 0.008), with no significant GH dose effect. BMC increased predominantly at the lumbar spine (11.0 +/- 10.6%, P = 0.015) rather than at the femoral neck or hip. In contrast, a significant dose-dependent increase was seen in IGF-I concentrations (adult dose: 114.5 +/- 119.4 microg/liter; pediatric dose: 178.5 +/- 143.7 microg/liter; P = 0.023). There were no gender-related differences in BMC changes with either dose, whereas the IGF-I increase was significantly higher with the pediatric than with the adult dose in females (P < 0.001) but not males (P = 0.606). In summary, reinstitution of GH replacement after final height in severely GH-deficient patients induced significant progression toward peak bone mass. Although there was a by-gender dose effect on IGF-I concentration, the treatment effect on bone was obtained in both males and females with the adult GH dose regimen.

Decreased quality of life in adult patients with growth hormone deficiency compared with general populations using the new, validated, self-weighted questionnaire, questions on life satisfaction hypopituitarism module.

To develop reference ranges for the Questions on Life Satisfaction Hypopituitarism Module (QLS-H), a new quality of life questionnaire for patients with hypopituitarism, data from 8177 adults were collected in France, Germany, Italy, The Netherlands, Spain, the United Kingdom, and the United States QLS-H scores declined with age, were lower in females than males, and differed significantly among countries. From these reference ranges we derived equations for z-scores, which adjust for age, gender, and country. QLS-H results from 957 adults with GH deficiency (GHD) participating in clinical trials were analyzed. At baseline, QLS-H scores were lower in females and differed significantly among countries. QLS-H scores significantly increased after GH treatment (6-8 months), but differences by country persisted. Calculating z-scores for patients eliminated all gender and most country differences. Pooled z-scores (mean +/- SD) from all patients increased from -0.99 +/- 1.39 at baseline to -0.14 +/- 1.30 after GH treatment. Quality of life assessment in adults with GHD requires the use of z-scores to correct for age, gender, and country differences. This approach allows pooling of data from different cohorts and comparison with general populations. QLS-H scores in adults with GHD were significantly decreased at baseline and were almost normalized after 6-8 months of GH therapy.

Skeletal requirements for optimal growth hormone replacement in the transitional years.

In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone (GH) has both direct and indirect actions on bone remodelling and homeostasis. In this review, the discussion begins with the influence of childhood-onset growth hormone deficiency (CO-GHD) on bone mineral accretion. The limitations of methods of assessing bone mineral density (BMD) are highlighted and specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.

Body composition, IGF-I and IGFBP-3 concentrations as outcome measures in severely GH-deficient (GHD) patients after childhood GH treatment: a comparison with adult onset GHD patients.

If GH therapy of children with GH deficiency (GHD) has been adequate, body composition should be comparable to that of patients who have undergone normal childhood development and become hypopituitary thereafter. To assess this, body composition was determined in 92 patients with childhood onset (CO) GHD, aged 18-30 yr, who had been treated to final height with GH for 8.98 +/- 4.30 yr and had stopped treatment 1.57 +/- 1.20 yr previously, but who remained GHD (assessed by a GH stimulation test and IGF-I values). These were compared with 35 age-matched GH-naïve hypopituitary patients with adult onset (AO) GHD. Lean body mass, fat mass, and total bone mineral content were assessed by dual energy x-ray absorptiometry and corrected for actual height. CO patients were shorter (CO height, -1.18 +/- 1.16 SD score; AO height, -0.38 +/- 1.12 SD score; P < 0.001) and had lower body mass index (CO, 23.19 +/- 5.76 kg/m(2); AO, 28.9 +/- 6.27 kg/m(2); P < 0.001) than the AO group. Although there were gender differences, within genders CO patients had lower lean body mass, fat mass, and bone mineral content (P < 0.001 in all cases) compared with AO patients. Standard deviation scores for IGF-I (CO female, -9.2 +/- 3.1; AO female, -5.2 +/- 2.6; CO male, -6.4 +/- 2.7; AO male, -3.5 +/- 2.3; P < 0.001 within each gender) and IGFBP-3 (CO female, -3.5 +/- 2.5; AO female, -1.7 +/- 1.5; CO male, -2.8 +/- 2.0; AO male, -1.1 +/- 1.6; P < 0.001 within each gender) were significantly lower in the CO group. These results suggest that patients with CO GHD who were treated to final height suffer a significant maturational deficit despite GH replacement during childhood.

Short-term safety and efficacy of human GH replacement therapy in 595 adults with GH deficiency: a comparison of two dosage algorithms.

The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 microg/kg per day for 3 months increasing to 6 microg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 microg/kg per day for 3 months increasing to 12 microg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 +/- 4.33 vs. 3.58 +/- 4.69%; P = 0.006) but not overall for the 6-month period (4.38% +/- 5.34% vs. 5.21% +/- 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (-2.81% +/- 7.81% vs. -5.53% +/- 8.64%; P < 0.001) and overall for the 6-month period (-6.35% +/- 9.42% vs. -9.45% +/- 12.07%; P = 0.006). IGF-I SD score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 SD score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.

Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood.

OBJECTIVE: Human GH treatment of patients with childhood-onset (CO) growth hormone deficiency (GHD) ceases when they reach final height; this provides an opportunity to retest GH status in all patients before determining whether GH therapy will be required in adult life. At present, the diagnostic approach to these patients is not fully standardized. This study aimed to characterize a large group of previously GH-treated CO GHD patients and establish their GH status. PATIENTS AND METHODS: The multinational study included 167 patients diagnosed as GH deficient and treated with hGH to final height during childhood. Mean age was 19.2 years and mean height standard deviation score (SDS) was -1.08. Peak serum GH concentrations were determined in standard GH stimulation tests. IGF-I and IGFBP-3 concentrations were determined at a central laboratory and converted to SDS values by reference to a normal population. RESULTS: Using only a peak GH value of less than 3 microg/l (1 mg = 3 U) in stimulation tests as the cut-off, 133 (79.6%) patients would be classed as GH deficient. Using only an IGF-I value less than -2 SDS as the cut-off, 134 (80.2%) patients would be classed as GH deficient. However, by using both criteria there were 120 (71.9%) patients who were definitely severely GH deficient (group 1) and 20 (12.0%) who were not GH deficient (group 2), leaving 14 (8.4%) classed as GH deficient from IGF-I SDS only (group 3) and 13 (7.8%) classed as GH deficient from stimulation test only (group 4). There was no difference between the groups in height SDS or body mass index (BMI), but the GH-deficient patients tended to have been diagnosed at a younger age (group 1, 8.2 +/- 3.9; group 2, 10.0 +/- 4.0; P = 0.052). For patients classed as GH deficient compared with those not GH deficient, the percentage of males was lower (group 1, 64.2%; group 2, 90.0%; P = 0.022) and the percentage with multiple pituitary hormone deficiencies was higher (group 1, 81.7%; group 2, 20.0%; P < 0 .001), with the other two groups being intermediate in each case. Only the group classed as GH deficient by both criteria had a mean IGFBP-3 less than -2 SDS and both IGF-I SDS and IGFBP-3 SDS increased steadily across the four groups. CONCLUSIONS: A high percentage (71.9%) of these childhood-onset GH-deficient patients were still GH deficient in adult life and are likely to require further hGH treatment. While 12.0% could be classed as definitely no longer GH deficient, there are some patients who are intermediate (16.2%) and may be classed as GH deficient by one criterion but not the other. When GH stimulation test results and IGF-I concentration are discordant, the IGFBP-3 level does not establish diagnosis and the hGH treatment requirement of such patients remains a dilemma.

Human growth hormone replacement in adult hypopituitary patients: long-term effects on body composition and lipid status--3-year results from the HypoCCS Database.

The Hypopituitary Control and Complications Study is an international surveillance study evaluating efficacy and safety of GH therapy of adult GH-deficient patients in clinical practice. The present report examined baseline data from 1,123 adult onset (AO) and 362 childhood onset (CO) patients, as well as efficacy in 242 patients who had completed 3 yr of GH treatment. At study entry, mean height, body mass index, waist to hip ratio, and lean body mass were significantly (P < 0.001 for each) lower in CO compared with AO patients. After 3 yr on GH, lean body mass was significantly increased in AO males and females and CO males but not CO females, whereas fat mass was significantly decreased in AO males only. Serum total cholesterol was decreased in females (-0.32 +/- 1.00 mmol/liter; P = 0.045) and males (-0.36 +/- 0.96 mmol/liter; P = 0.004). High-density lipoprotein (HDL) cholesterol was increased for females (0.10 +/- 0.26 mmol/liter; P = 0.026) and males (0.10 +/- 0.34 mmol/liter; P = 0.022). The low-density lipoprotein/HDL ratio was decreased in AO males (-0.93 +/- 2.00; P = 0.003), AO females (-0.65 +/- 0.74; P < 0.001), and CO females (-0.69 +/- 0.76; P = 0.038), but the decrease in CO males was not significant (-0.84 +/- 2.85; P = 0.273). In AO patients, lean body mass increase from baseline was greatest in the those younger than 40 yr old, less but still significant in the middle group (40-60 yr) and unchanged in older (>60 yr) patients; conversely, decreases in the low-density lipoprotein/HDL ratio were small and not significant in the younger patients but greater and significant in the middle and older age groups. During the 3-yr treatment, 114 (7.7%) patients discontinued, including 9 (0.6%) for tumor recurrences, 9 (0.6%) for neoplasia, and 9 (0.6%) for side effects. Therefore, these observational data showed significant long-term efficacy of adult GH replacement therapy on body composition and lipid profiles and indicate that age is an important predictor of response.