GH-deficient Adolescents Research Articles

Gender-Dependent Growth and Insulin-Like Growth Factor-1 Responses to Growth Hormone Therapy in Prepubertal Growth Hormone-Deficient Children.

Gender seems to be an important factor influencing the response to recombinant human growth hormone (rhGH) therapy in GH-deficient adolescents and adults. The results of studies evaluating gender-specific response to rhGH therapy in prepubertal GH-deficient children are divergent. The aim of this study was to determine the effect of gender on the growth and insulin-like growth factor-1 (IGF-1) responses in 75 prepubertal GH-deficient children during the first 2 years of rhGH therapy. There were no baseline gender differences in age, bone age, anthropometrical parameters, and IGF-1 SDS for bone age. After the initiation of rhGH therapy, there were no gender-specific differences concerning the reduction of height deficit. Serum IGF-1 levels were higher in the prepubertal GH-deficient girls than in the age-matched boys, but the difference was not significant when expressed as IGF-1 SDS for bone age. The increase in IGF-1 SDS for bone age was significantly greater in girls versus boys after the first 6 months of therapy, comparable between girls and boys after the first year of therapy, and tended to be higher in boys after the second year of therapy. In conclusion, prepubertal GH-deficient girls and boys do not differ significantly in growth response in the first 2 years of rhGH therapy.

Physician decisions to discontinue long-term medications using a two-stage framework: the case of growth hormone therapy.

Physician decisions to discontinue prescription medications for chronic conditions are fundamental determinants of drug use but have been inadequately studied. The decision to stop growth hormone (GH) therapy is an important example because of high cost (approximately $26,000/y for a 48-kg child), complexity of treatment options, and expansion of patient populations. The aim of this study was to identify the factors that influence physician recommendations in the process of discontinuing therapy. A random sample of half of U.S. pediatric endocrinologists (n = 265) was mailed a survey that included case scenarios of GH-deficient adolescents. Decision options involved a 2-stage framework to 1) initiate change in ongoing GH therapy (by discussing discontinuing GH with the family but not yet stopping treatment), and 2) take action to discontinue ongoing GH therapy (by terminating GH or reducing the dose to adult maintenance level). Physician recommendations. The response rate was 83.8%. Physiological indices of growth potential (growth velocity, bone age) significantly influenced discontinuation decisions (both P < 0.001). However, family preference, child's height, and physician attitudes exerted independent effects (each P < 0.05). Treatment price had little influence. Together, these variables accounted for 60% to 70% of the variation in recommendations. Their relative influence differed by stage in the discontinuation process. The variables in our framework substantially explain discontinuation decisions. The data demonstrate the importance of both physiological and nonphysiological factors. The results suggest that physicians value even small gains as final height approaches, although an additional 20% expenditure may be needed to gain the last 1% to 3% of adult height.

Sperm analysis in growth hormone-deficient adolescents previously treated with an aromatase inhibitor: Comparison with normal controls

We performed two semen analyses in each of a small cohort of 11 GH-deficient (GHD) adolescents (mean age 18.1 +/- 0.6 yrs), previously treated (mean 29 months prior) with either GH alone or GH and an aromatase inhibitor (anastrozole) for 12 months and compared their data with those of 10 healthy controls (mean age 18.7 +/- 1.8 yrs). Although some adolescents had lower sperm parameters as compared to adult reference values, mean sperm concentrations, motility, and morphology were comparable among the 3 groups, suggestive that this small group of GHD adolescents previously treated with anastrozole has descriptively similar sperm parameters as other GHD and GH-sufficient adolescent controls.

Endothelial Function, Carotid Artery Intima-Media Thickness, Epicardial Adipose Tissue, and Left Ventricular Mass and Function in Growth Hormone-Deficient Adolescents: Apparent Effects of Growth Hormone Treatment on These Parameters

The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years. Ten GHD children on GH treatment with a chronological age (CA) of 14.6 +/- 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 +/- 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls. Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P < 0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents. GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

Limited Efficacy of Growth Hormone (GH) during Transition of GH-Deficient Patients from Adolescence to Adulthood: A Phase III Multicenter, Double-Blind, Randomized Two-Year Trial

Treatment of GH-deficient adolescents in transition to adulthood remains challenging. The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition. Fifty-eight GH-deficient adolescents (mean age, 15.8 +/- 1.8 yr; 33 males) at near completion of their linear growth participated in the study. Baseline studies were done while subjects were on GH. Subjects were retested (insulin-induced hypoglycemia) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls (n = 18). GH-deficient subjects were randomized to GH (n = 25, approximately 20 microg/kg.d) or placebo (n = 15). The multicenter study was conducted over a 2-yr period. Changes in body composition, bone mineral density (BMD), quality of life (QOL), cardiovascular and metabolic markers were measured. All groups had normal measures of lipid and carbohydrate metabolism, body composition, BMD, cardiac function, muscle strength, and QOL at baseline and after 2 yr. IGF-I concentrations decreased in all, but less so in the GH-group (P = 0.013). There was a greater increase in lean body mass (lesser adiposity) in the GH group than placebo at 12 months, but not at 24 months. 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, carbohydrate and lipid metabolism, and QOL when reaching adult height; and 2) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects. GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr. Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood.

Authors’ Response: The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth

Authors’ Response: The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth

The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth

The Effect of Cessation of Growth Hormone (GH) Therapy on Bone Mineral Accretion in GH-Deficient Adolescents at the Completion of Linear Growth

Cardiac Mass and Function, Carotid Artery Intima-Media Thickness, and Lipoprotein Levels in Growth Hormone-Deficient Adolescents

The objective of our study was to evaluate whether cardiac mass and function, carotid artery intima-media thickness, and serum lipid and lipoprotein(a) levels are abnormal in adolescents with GH deficiency. Young adults with childhood-onset and adulthood-onset GH deficiency have been found to have a higher cardiovascular risk, as manifested among other factors by reduced left ventricular mass, impaired systolic function, significant increase in arterial intima-media thickness, and dyslipidemia. Twelve adolescents (seven males and five females) with GH deficiency (10 idiopathic and 2 organic), with an age of 14.2 ± 2.8 yr and a height of 140.6 ± 17.9 cm (height sd score,− 2.6 ± 0.3), were studied. Six children had received GH in the past but were off therapy for several years, whereas six patients had never been treated with GH. Fasting blood samples were obtained for serum lipids and lipoprotein(a) analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass, as well as left ventricular ejection fraction at rest and pulmonary venous flow velocities; carotid artery intima-media thickness was measured using high-resolution mode B ultrasound. Seven GH-deficient (GHD) adolescents on GH at the time of the study and 19 healthy adolescents, all comparable for age, pubertal status, height, weight, blood pressure, and pulse, participated in this study as controls. Interventricular septal thickness (6.5 ± 1.3 vs. 7.0 ± 1.5 mm), left ventricular posterior wall thickness (7.0 ± 1.8 vs. 7.5 ± 2.0 mm), and left ventricular mass after correction for body surface area (71.2 ± 21.8 vs. 70.7 ± 18.0 g/m2) were similar in untreated GHD patients and healthy controls. Similarly, the left ventricular ejection fraction at rest was similar in untreated GHD subjects and controls (70.0 ± 0.7 vs. 70.0 ± 0.6%), as were the pulmonary venous flow velocities (0.54 ± 0.16 vs. 0.55 ± 0.10 m/s for diastolic peak velocity; 0.51 ± 0.16 vs. 0.50 ± 0.09 m/s for systolic peak velocity; and 0.19 ± 0.06 vs. 0.19 ± 0.05 m/s for atrial reversal filling). Carotid artery intima-media thickness (0.60 ± 0.02 mm and 0.59 ± 0.02 mm for the right and left carotid arteries, respectively) was also normal in our untreated GHD patients when compared with healthy controls. In addition, all echocardiographic measurements were similar in GHD subjects on or off GH at the time of the study. Low-density lipoprotein cholesterol levels were increased in untreated GHD patients when compared with healthy controls (3.17 ± 0.70 vs. 2.33 ± 0.36 mmol/L; P < 0.01), whereas total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were similar to that of controls. Total cholesterol levels were increased in our untreated GHD adolescents when compared with GHD subjects receiving GH therapy at the time of the study, while low-density lipoprotein cholesterol and triglyceride levels were also elevated, although not significantly. Lipoprotein(a) levels were elevated in untreated GHD adolescents when compared with healthy controls, and untreated GHD subjects had higher lipoprotein(a) concentrations than GH-treated patients. GHD adolescents, regardless of whether or not they received GH therapy, do not seem to show alterations in cardiac mass and function or early atherosclerotic changes. They must, however, be followed carefully because they already present cardiovascular risk factors such as dyslipidemia, which may increase their cardiovascular morbidity over time.

Cardiac mass and function, carotid artery intima-media thickness, and lipoprotein levels in growth hormone-deficient adolescents.

The objective of our study was to evaluate whether cardiac mass and function, carotid artery intima-media thickness, and serum lipid and lipoprotein(a) levels are abnormal in adolescents with GH deficiency. Young adults with childhood-onset and adulthood-onset GH deficiency have been found to have a higher cardiovascular risk, as manifested among other factors by reduced left ventricular mass, impaired systolic function, significant increase in arterial intima-media thickness, and dyslipidemia. Twelve adolescents (seven males and five females) with GH deficiency (10 idiopathic and 2 organic), with an age of 14.2 +/- 2.8 yr and a height of 140.6 +/- 17.9 cm (height SD score, -2.6 +/- 0.3), were studied. Six children had received GH in the past but were off therapy for several years, whereas six patients had never been treated with GH. Fasting blood samples were obtained for serum lipids and lipoprotein(a) analysis. Patients underwent transthoracic M-mode and two-dimensional echocardiographic evaluation for measurement of interventricular septal thickness, left ventricular posterior wall thickness, and left ventricular mass, as well as left ventricular ejection fraction at rest and pulmonary venous flow velocities; carotid artery intima-media thickness was measured using high-resolution mode B ultrasound. Seven GH-deficient (GHD) adolescents on GH at the time of the study and 19 healthy adolescents, all comparable for age, pubertal status, height, weight, blood pressure, and pulse, participated in this study as controls. Interventricular septal thickness (6.5 +/- 1.3 vs. 7.0 +/- 1.5 mm), left ventricular posterior wall thickness (7.0 +/- 1.8 vs. 7.5 +/- 2.0 mm), and left ventricular mass after correction for body surface area (71.2 +/- 21.8 vs. 70.7 +/- 18.0 g/m(2)) were similar in untreated GHD patients and healthy controls. Similarly, the left ventricular ejection fraction at rest was similar in untreated GHD subjects and controls (70.0 +/- 0.7 vs. 70.0 +/- 0.6%), as were the pulmonary venous flow velocities (0.54 +/- 0.16 vs. 0.55 +/- 0.10 m/s for diastolic peak velocity; 0.51 +/- 0.16 vs. 0.50 +/- 0.09 m/s for systolic peak velocity; and 0.19 +/- 0.06 vs. 0.19 +/- 0.05 m/s for atrial reversal filling). Carotid artery intima-media thickness (0.60 +/- 0.02 mm and 0.59 +/- 0.02 mm for the right and left carotid arteries, respectively) was also normal in our untreated GHD patients when compared with healthy controls. In addition, all echocardiographic measurements were similar in GHD subjects on or off GH at the time of the study. Low-density lipoprotein cholesterol levels were increased in untreated GHD patients when compared with healthy controls (3.17 +/- 0.70 vs. 2.33 +/- 0.36 mmol/L; P < 0.01), whereas total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were similar to that of controls. Total cholesterol levels were increased in our untreated GHD adolescents when compared with GHD subjects receiving GH therapy at the time of the study, while low-density lipoprotein cholesterol and triglyceride levels were also elevated, although not significantly. Lipoprotein(a) levels were elevated in untreated GHD adolescents when compared with healthy controls, and untreated GHD subjects had higher lipoprotein(a) concentrations than GH-treated patients. GHD adolescents, regardless of whether or not they received GH therapy, do not seem to show alterations in cardiac mass and function or early atherosclerotic changes. They must, however, be followed carefully because they already present cardiovascular risk factors such as dyslipidemia, which may increase their cardiovascular morbidity over time.

High Dose Recombinant Human Growth Hormone (GH) Treatment of GH-Deficient Patients in Puberty Increases Near-Final Height: A Randomized, Multicenter Trial1

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, GH-deficient children have been dosed on a standard per kg BW basis similar to prepubertal children. This randomized study was designed to compare the efficacy and safety of standard recombinant human GH (rhGH) therapy (group I, 0.3 mg/kg x week) vs. high dose therapy (group II, 0.7 mg/kg x week) in GH-deficient adolescents previously treated with rhGH for at least 6 months. Ninety-seven children with documented evidence of GH deficiency (peak GH in response to stimuli, <10 ng/mL), with either organic or idiopathic pathology, were recruited. Both groups were matched for sex (group I, 42 males and 7 females; group II, 41 males and 7 females), age [group I, 14.0+/-1.6 (+/-SD) yr; group II, 13.7+/-1.6], standardized height (group I, -1.4+/-1.1; group II, -1.2+/-1.1), bone age (group I, 13.1+/-1.3 yr; group II, 13.1+/-1.3) etiology, maximum stimulated GH, previous growth rate, and midparental target height. All subjects were in puberty (Tanner stage 2-5) at study entry. Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7+/-0.9 in the standard dose group and 0.0+/-1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5+/-5.3 cm (group I) vs. 25.1+/-4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8+/-4.2 cm (group I) vs. 8.4+/-5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 microg/L (range, 204-649) in group I and 435 microg/L (range, 104-837) in group II; at 36 months they were 651 microg/L (range, 139-1079) in group I vs. 910 microg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups. In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.

Effects of High Dose rhGH Therapy in Adolescent Children with GH Deficiency: A Randomized, Multicenter Study • 460

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, pubertal GH-deficient children have been dosed on a standard per kg body weight basis similarly to prepubertal children. This study was designed to compare the efficacy and safety of conventional (Group I (GI), 0.3 mg/kg.w) vs high dose rhGH Rx (Group II (GII), 0.7 mg/kg.w), in GH-deficient adolescents treated with rhGH for at least 6 mo. 97 children with evidence of GH deficiency (poor linear growth, peak GH to stimuli < 10 μg/L, organic and idiopathic), were recruited. The groups were matched for sex (I:42M, 7F; II: 41M, 7F), age (I: 14.0±1.6 (SD) yrs; II: 13.7±1.6), height SDS (I: -1.4±1.1; II:-1.2±1.1), bone age (BA) (I: 13.2±1.3 yrs; II: 13.1±1.3) and etiology, maximum stimulated GH, previous growth rate and mid-parental target height (Ht). All were in puberty (mean: Tanner Stage 3). Differences from baseline (Δ) were available at 12, 24 and 30 mo. The Δ growth velocity (cm/y) at 12 mo: -0.3±2.5 (I), +1.3±2.8 (II), p=0.005; at 30 mo: -3.8±2.9 (I),-2.0±3.4 (II), p=0.07; Δ Ht (cm): 12 mo: 8.2±2.3 (I), 9.9±2.1 (II), p=0.0004; 30 mo: 18.6±4.7 (I), 21.8±4.8 (II), p=0.02; Δ Bailey-Pinneau predicted Ht (cm): 12 mo: 1.1±4.6 (I), 3.3±4.9 (II), p=0.03; 30 mo: 4.4±5.4 (I), 7.7±6.8 (II), p=0.17. Δ IGF-I: 12 mo: 131±238 μg/L (I), 175±317 (II), p=0.89; 30 mo: 257±255(I), 329±411 (II), p=0.92. No differences in Δ BA were detected between groups at any interval: 30 mo: 2.6±1.2 (I), 2.6±1.1(II), p=0.94. In boys treated ≥2 yrs, the Δ Ht was 4cm greater in the high-dose group. High dose rhGH was well tolerated with no difference in HbA1c or glucose concentrations between groups. Plasma insulin concentrations were higher in GII (p=0.01). In summary: Preliminary analysis shows that as compared to conventional treatment, high dose rhGH Rx in adolescents: 1-increased Ht and Ht SDS scores significantly; 2-did not advance skeletal maturation; 3-appeared to be well tolerated and safe. We conclude: High dose rhGH Rx improves the final adult Ht gain in GH-deficient patients in puberty, without increasing the rate of bone maturation.

Insulin-like growth factors (IGF) I and II and IGF binding proteins 1, 2 and 3 during low-dose growth hormone (GH) infusion and sequential euglycemic and hypoglycemic glucose clamps: studies in GH-deficient patients

To evaluate the short-term effects of growth hormone (GH), insulin and different levels of glycemia on insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBP) 1, 2 and 3, we studied six GH-deficient adolescents during a night and the following day in the postabsorptive (basal) state followed by sequential euglycemic (5 mmol/l) and hypoglycemic (3 mmol/l) glucose clamps concomitant with an intravenous infusion (starting at 24.00 h) of GH (35 micrograms/h) or saline. Current GH therapy was withdrawn 24 h prior to each study. Nocturnal levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 remained stable during both studies. Nocturnal serum IGFBP-1 increased and correlated inversely with insulin in both studies. Regression analysis revealed a significant inverse correlation between mean nocturnal IGFBP-2 and IGFBP-3 levels. During the daytime, serum IGF-I declined slowly during saline infusion, whereas serum IGF-II remained stable in both studies. Serum IGFBP-1 displayed a gradual significant decline during the basal state and the euglycemic and hypoglycemic clamps seemed to be unaffected by GH levels. By contrast, serum IGFBP-2 remained stable during the same period in both the GH and the saline study. Serum IGFBP-3 declined insignificantly during the daytime in the saline study.(ABSTRACT TRUNCATED AT 250 WORDS)