Cessation Of Growth Hormone Treatment Research Articles

Growth Hormone Treatment, Cardiovascular Risk and Autonomic Maturation in Children and Adolescents with Growth Hormone Deficiency or Born Small for Gestational Age

Introduction: The impact of growth hormone therapy in children with short stature on cardiovascular prognosis seems to be unpredictable from big databases. The enhanced cardiovascular risk in this group of patients may be related to adverse autonomic imprinting by early life stress. Autonomic dysfunction and possible effects of growth hormone therapy on the autonomic nervous system can be measured easily by calculating heart rate variability (HRV) from Holter electrocardiogram monitoring. Methods: We performed HRV analysis prior to growth hormone therapy (N = 33), within the first year of growth hormone therapy between 4 and 10 years of age (N = 19), at least a further HRV measurement between 10 and 15 years (N = 30). Additional measurements were performed before and after cessation of growth hormone therapy (N = 14). Data were compared to untreated pediatric patients with short stature and to age matched healthy controls. Results: Untreated patients with short stature due to growth hormone deficiency or intrauterine growth restriction in early childhood have significantly increased heart rates most of all at night and concomitantly reduced global HRV indicated as Standard Deviation of Normal to Normal Intervals (SDNN). Growth hormone treated adolescents and the untreated patients with short stature show significantly elevated mean heart rates and concomitantly reduced vagus activities measured as reduced Route Mean Square Standard Deviation (RMSSD). After cessation of growth hormone treatment SDNN significantly increases and heart rate decreases to normal values in formerly treated patients with catch-up growth. Conclusion: There is a comparable autonomic dysfunction in treated and untreated children with short stature as an indicator for enhanced cardiovascular risk. After cessation of growth hormone therapy, we found a significant improvement of reduced HRV to normal values.

Cardiovascular risk factors and carotid intima media thickness in young adults born small for gestational age after cessation of growth hormone treatment: a 5-year longitudinal study

Whereas most SGA children experience spontaneous catch-up growth leading to the achievement of normal adult height, approximately 10% remain short and are candidates for GH therapy. SGA subjects have increased cardio-metabolic disease risk [17] and the effects of GH treatment on blood pressure, body composition, glucose metabolism and lipid profile have been investigated [18]. Recently, interest has been focused on the cardiovascular disease risk in adults treated with GH during childhood. Data from the French SAGhE (Safety and Appropriateness of GH therapy in Europe) study cohort have shown increased cerebrovascular mortality rate [19], although not confirmed in other SAGhE cohorts [20]. In theory, children born SGA, having intrinsic higher cardio-metabolic risk, might be at even higher risk if exposed to long-term GH therapy.

Body composition and metabolic health of young male adults with childhood-onset multiple pituitary hormone deficiency after cessation of growth hormone treatment.

Recombinant human growth hormone (rhGH) replacement therapy is usually stopped after linear growth completion in patients with growth hormone deficiency. In patients with multiple pituitary hormone deficiency (MPHD), the long-term effects of discontinuation of rhGH replacement are unknown. In this study, the anthropometric and metabolic parameters of 24 male patients with adult growth hormone deficiency (AGHD) due to MPHD in childhood after cessation of rhGH therapy for a mean of 7.1 years were measured and compared with 35 age-matched controls. Body composition was evaluated by bioelectrical impedance analysis (BIA). In the AGHD group, body mass index (BMI) was significantly increased and 29.2% had obesity. The AGHD group had a 17.7 cm increase in waist circumference (WC). The fat free mass (FFM) was significantly lower in the AGHD group. Both the fat mass (FM) and percentage of fat mass (FM%) were significantly increased in the AGHD group. Both the systolic blood pressure (BP) and diastolic pressure were significantly lower in AGHD group. The lipid profile was generally similar in both groups, except for a decrease of high density lipoprotein-cholesterol (HDL-C) in the AGHD group. There was significant hyperuricemia in the AGHD group. Cessation of rhGH leads to a significant increase of FM in early adulthood in male patients with childhood-onset MPHD (CO-MPHD).

Cardiovascular risk factors and carotid intima media thickness in young adults born small for gestational age after cessation of growth hormone treatment: a 5-year longitudinal study

Growth hormone treatment reduces blood pressure and lipid concentrations. We assessed long-term changes in blood pressure, lipid concentrations, and carotid intima media thickness over a 5-year period after cessation of growth hormone treatment in adults born small for gestational age. We did a longitudinal observational study at a medical centre in the Netherlands between April 1, 2004, and April 1, 2016. We included adults born small for gestational age who were treated with growth hormone (1 mg/m2 per day); treatment started during childhood until adult height. Participants were evaluated at cessation of treatment, and 6 months, 2 years, and 5 years later. We compared cardiovascular risk factors with untreated controls from the PROGRAM study. We included 199 participants born small for gestational age and treated with growth hormone along with 285 controls: 51 untreated short adults born small for gestational age, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age. In the 6 months after treatment cessation, systolic blood pressure increased temporarily from 113·00 mm Hg (95% CI 111·18-114·82) to 116·92 mm Hg (115·07 to 118·77; p<0·001) and diastolic blood pressure increased temporarily from 62·19 mm Hg (60·99-63·38) to 66·51 mm Hg (65·14-67·89; p<0·001). At 5 years after treatment cessation, mean systolic blood pressure was 109·2 mm Hg (105·5-113·0) and mean diastolic blood pressure was 63·4 mm Hg (60·9-65·9), similar to the values at cessation. Lipid concentrations were non-significantly higher 5 years after treatment cessation (p values 0·09-0·21) than at treatment cessation. Cessation of growth hormone had no effect on carotid intima media thickness. At 5 years after cessation, total cholesterol was lower in adults treated with growth hormone (mean 4·21 mmol/L, 95% CI 4·04-4·38) than in untreated short adults born small for gestational age (4·66 mmol/L, 4·42-4·92; p=0·0030), as was mean LDL cholesterol (2·28 mmol/L, 2·14-2·43 vs 2·85 mmol/L, 2·62-3·10; p<0·0001); blood pressure and carotid intima media thickness did not differ between these two groups (p values >0·12). At 5 years after cessation, systolic blood pressure, diastolic blood pressure, lipid concentrations, and carotid intima media thickness of adults treated with growth hormone were not different to those in adults born small for gestational age who had spontaneous catch-up growth or adults born appropriate for gestational age. Long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on cardiovascular health in early adulthood and improves lipid profiles. Novo Nordisk (Netherlands).

Cardiovascular risk after cessation of growth hormone treatment in people born small for gestational age

Cardiovascular risk after cessation of growth hormone treatment in people born small for gestational age

Metabolic health of young adults who were born small for gestational age and treated with growth hormone, after cessation of growth hormone treatment: a 5-year longitudinal study

Growth hormone treatment reduces fat mass and insulin sensitivity and increases lean body mass. Data are only available for short-term longitudinal changes after cessation of growth hormone treatment in young adults born small for gestational age. We aimed to assess long-term changes over a 5-year period following cessation of growth hormone treatment. We did a longitudinal study of young adults born small for gestational age and previously treated with growth hormone. Individuals were followed up for 5 years after attainment of adult height, when growth hormone treatment was discontinued: assessments were done at cessation of growth hormone treatment and at 6 months, 2 years, and 5 years thereafter. Data 5 years after cessation of growth hormone were compared with untreated age-matched controls. We used dual-energy x-ray absorptiometry to assess body composition, and did frequently sampled intravenous glucose tolerance tests to assess insulin sensitivity, acute insulin response, and the disposition index (a measure of β-cell function). This study is registered with ISRCTN, numbers ISRCTN96883876 and ISRCTN65230311. Between April, 2004, and April, 2016, we followed up 199 young adults born small for gestational age and previously treated with growth hormone, during the 5 years after cessation of growth hormone treatment. Data at 5 years for these individuals were compared with those for 51 untreated adults born small for gestational age with short stature, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age and unexposed to growth hormone treatment. In young adults born small for gestational age and previously treated with growth hormone, 5 years after cessation of growth hormone treatment, there were increases in fat mass (estimated marginal mean 10·73 kg [95% CI 9·95-11·50] at cessation of treatment vs 16·12 kg [14·77-17·46] at 5 years; p<0·0001), trunk fat (5·34 kg [4·94-5·73] vs 7·86 kg [7·12-8·60]; p<0·0001), and limb fat (4·87 kg [4·49-5·25] vs 7·41 kg [6·78-8·05]; p<0·0001); furthermore, lean body mass had decreased (42·41 kg [95% CI 41·09-43·73] at cessation of treatment vs 41·42 kg [40·17-42·66] at 5 years; p=0·0013). Insulin sensitivity increased within 6 months of cessation and was sustained 5 years after treatment cessation (estimated marginal mean 4·14 mU/L [95% CI 3·79-4·53] at cessation of treatment vs 6·15 mU/L [5·21-7·24] at 5 years; p<0·0001), and acute insulin response was diminished at 6 months, which persisted at 5 year follow-up (597·63 mU/L [539·62-661·86] vs 393·69 mU/L [337·56-459·15]; p<0·0001). The disposition index was increased 6 months after treatment but values at 5 years were similar to those at cessation of treatment (2483·94 [95% CI 2233·43-2762·54] at cessation of treatment vs 2367·83 [2033·43-2757·22] at 5 years; p=0·49). 5 years after cessation of growth hormone treatment, adults born small for gestational age and previously treated with growth hormone had fat mass, insulin sensitivity, and disposition index similar to those of untreated adults born small for gestational age with short stature, but lean body mass (adjusted for sex and height) was lower (46·47 kg [44·95-48·00] in those born small for gestational age with short stature vs 44·32 kg [43·35-45·30] in those born small for gestational age and treated with growth hormone; p=0·007). In adults previously treated with growth hormone born small for gestational age, at 5 years after cessation of growth hormone treatment, compared with adults born small for gestational age with spontaneous catch-up growth and adults born appropriate for gestational age, lean body mass was lower and results from frequently sampled intravenous glucose tolerance tests were similar. Significant changes in body composition and insulin sensitivity were recorded 5 years after cessation of growth hormone treatment in adults born small for gestational age, reflecting a loss of pharmacological effects of growth hormone. 5 years after cessation of treatment, fat mass, insulin sensitivity, and β-cell function of previously treated adults were similar to untreated adults born small for gestational age with short stature, indicating that long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on metabolic health in early adulthood. Novo Nordisk Farma BV (Netherlands).

Exacerbation of BMI after cessation of growth hormone therapy in patients with Prader–Willi syndrome

Long-term treatment with growth hormone (GH) in patients with Prader-Willi syndrome (PWS) improves not only height velocity, height standard deviation score, and final height, but also the degree of obesity and body composition abnormalities. Anecdotally, PWS patients tend to suffer from severe obesity and its complications after cessation of GH therapy. However, there have been no studies to investigate changes in body mass index (BMI) and adipose tissue distribution after cessation of GH therapy in young PWS patients. Therefore, we investigated changes in the BMI-standard deviation score (SDS) and adipose tissue distribution after cessation of GH therapy in PWS patients. We evaluated 14 PWS patients. BMI-SDS was calculated at 0, 6, 12, 18, and 24 months before and after cessation of GH treatment. We also evaluated subcutaneous adipose tissue (SAT) (cm(2)) and visceral adipose tissue (VAT) (cm(2)) area in 8 of the 14 study patients with single slice abdominal computed tomography at the level of the umbilicus. The BMI-SDS significantly increased at 6, 12, 18, and 24 months after cessation of GH therapy (P = 0.039, P = 0.008, P = 0.003, P = 0.003, respectively). There was a tendency toward increases in VAT at 12 and 24 months after cessation of GH therapy, but the increases did not reach statistical significance (P = 0.062, P = 0.125, respectively). Therefore, cessation of GH therapy in PWS patients worsened BMI. To maintain good body composition and prevent complications of obesity, long-term use of GH in adult PWS patients may be advisable.

Early Changes in Body Composition After Cessation of Growth Hormone Therapy in Childhood-Onset Growth Hormone Deficiency

At final height, somatic maturity has not been reached yet. We investigated bone and body composition in patients, who completed pediatric growth hormone (GH) treatment at final height. After a mean period of 0.55 ± 0.17 yr off GH treatment 90 (66 m/24 f) childhood-onset growth hormone deficiency (GHD) patients were reinvestigated for GHD by insulin tolerance testing at a mean age of 17.52 ± 1.50 yr. Thirty-seven (25 m/12 f) patients remained GH deficient (persistent GHD). Bone and body composition were measured using peripheral quantitative computed tomography of the nondominant forearm. Bone mineral density (BMD) was within normal limits. Total cross-sectional bone area Z-score (0.64 ± 1.3) was significantly higher as a result of an enlarged medullary cavity Z-score (1.12 ± 1.2) leading to reduction of cortical thickness Z-score (−1.21 ± 1.0). Patients with persistent GHD had a significantly higher fat mass (13.3 ± 8.7 and 6.8 ± 4.6 cm 2, p < 0.05), which was more pronounced in multiple pituitary hormone deficiency patients. Shortly after cessation of GH treatment in patients treated for childhood-onset GHD age adequate normal BMD and enlarged diaphysis was detectable. Patients with persistent GHD status had a significant higher fat mass.

Longitudinal Changes in Insulin Sensitivity and Body Composition of Small-For-Gestational-Age Adolescents after Cessation of Growth Hormone Treatment

GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, beta-cell function, and body composition change over time after stopping GH treatment. Our objective was to investigate longitudinal changes in Si, beta-cell function, and body composition after cessation of long-term GH treatment. We conducted a longitudinal study that included 48 SGA adolescents studied at adult height, while still on GH, and 6 months after GH stop and compared them with 38 appropriate-for-gestational-age (AGA) controls at both time points. We took paired measurements of Si and beta-cell function, assessed by frequently sampled iv glucose tolerance tests with tolbutamide, and body composition, measured by dual-energy x-ray absorptiometry. After stopping GH, Si (P = 0.006), glucose effectiveness (Sg; P = 0.009) and beta-cell function (disposition index; P = 0.024) increased, whereas insulin secretion (acute insulin response; not significant) decreased. Fat percentage increased (P < 0.0005), and lean body mass decreased (P < 0.0005), but fat distribution remained unaltered, and body composition remained within the normal range. Compared with AGA controls, Si was lower during GH and became similar after GH stop, acute insulin response was higher at both time points, and glucose effectiveness and disposition index became higher. The GH-induced lower Si in SGA adolescents increases after stopping long-term GH treatment and becomes similar to that of AGA controls. Discontinuation of GH treatment is, however, also associated with an increase in percent body fat and with a decrease in lean body mass, without changes in fat distribution.

Cognitive, emotional, physical and social effects of growth hormone treatment in adults with Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by short stature, muscular hypotonia, hyperphagia, obesity, maladaptive behaviour, hypogonadism and partial growth hormone (GH) deficiency (GHD). Severe GHD of other aetiologies has been shown to affect mood and quality of life negatively, and there are reports of improvements with GH replacement. We have studied cognitive, emotional, physical and social parameters in PWS adults at baseline, during and after GH treatment. Nineteen patients, 9 females and 10 males, median age 25 years, mean BMI 35 kg/m2 participated in this study. Approximately half of the group had GHD. All patients fulfilled the clinical criteria for PWS and 13 had a positive genotype. The patients were randomized to 6 months of treatment with either GH [1.6 IU/day (0.53 mg/day)] or placebo, followed by 12 months of active GH treatment. Treatment was then stopped, and the patients were followed for an additional period of 6 months. A test battery for general cognitive evaluation and a computer-based measurement of reaction time, motor speed and fluency were employed at baseline, after 6 months and at the end of GH treatment. At the same time intervals, a self-evaluation questionnaire was answered at the end of each test session. Other questionnaires reflecting the patients' cognitive, emotional, physical and social status were answered by relatives/caretakers at baseline and at 3 and 6 months following cessation of GH treatment. Baseline cognitive level was estimated to be moderately to mildly impaired; IQ range was 40-90. The results from some of the cognitive and the motor performance tests improved significantly after 6 and 18 months of GH treatment. According to the questionnaires, both the patients and the relatives/caretakers evaluated physical status rather negatively at baseline, but still, impairments in both physical and social status and overall functioning were observed when GH treatment was discontinued. The self-evaluation did not change in any aspect during GH treatment. In this pilot study of an adult PWS cohort, we were able to document beneficial effects in mental speed and flexibility and in motor performance during GH treatment. Impairment was seen in physical and social status as well as overall functioning, when GH treatment stopped. Studies of larger cohorts are needed to further elucidate the role of GH treatment in this group of patients.

Growth hormone outgrows growth.

Growth hormone (GH) replacement has been offered to GH-deficient (GHD) children for approximately 40 years whereas it has only been a licensed indication for the treatment of GHD adults since 1996. Nonetheless, the advent of GH replacement for adult GHD patients (Jorgensen et al., 1989; Salomon et al., 1989) has proved informative about the overall management of the GHD child and teenager; equally, the longstanding experience of the paediatric endocrinologist with GH replacement has provided some guidance about potential pitfalls in the diagnosis and management of the adult GHD patient. It is the knowledge exchange at this professional interface that forms the focus of this article.

The effect of growth hormone therapy on mandibular and cranial base development in children treated with total body irradiation.

The aim of the present investigation was to study craniomandibular development during growth hormone (GH) therapy in nine girls and one boy, aged between 7.3 and 16 years, who exhibited pronounced growth reduction after total body irradiation (TBI) and bone marrow transplantation (BMT). Age- and sex-matched healthy children with normal dentofacial development constituted the control material. The investigation data were based on measurements made on lateral skull radiographs taken at the start and, on average, 6 months after cessation of GH treatment. The control group comprised similar longitudinal cephalographic records. The results showed that GH therapy in patients who exhibited growth retardation after TBI and BMT had only a minor effect on cranial base dimensions, probably due to the fact that the development of this area is completed at a relatively early age. The effect of GH treatment on mandibular growth was very obvious. The dimensional increase of the mandibular variables in the patients was equivalent to, or in some cases even exceeded, that of the controls. In relation to basion, the mandibular condyles were displaced in a backward/upward direction in the patient group. Displacement in the opposite direction was recorded in the controls. It seems likely that the development seen in the patients is a reflection of a normalization of the condyle-fossa relationship made possible by enhanced condylar growth. This change should be advantageous for the function of the craniomandibular complex.

Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects.

GH has many effects on metabolism in addition to promoting growth. We studied changes in body composition and lipid profiles during and after GH treatment in 94 children with GH deficiency. Sixty-two subjects (46 boys and 16 girls) were evaluated at the beginning and during 36 months of GH treatment. The other 32 (21 boys and 11 girls) who had already been treated with GH were examined after the discontinuation of GH for a 6-month period. The height SD scores at the beginning and the discontinuation of GH treatment were -2.81 and -1.34 in boys and -3.14 and -1.38 in girls, respectively. The percent body fat (BF) significantly decreased from 16.5% to 11.7% in boys and from 16.7% to 11.6% in girls during the first 6 months of GH treatment (P < 0.01). BF subsequently remained constant in boys, but started to increase in girls from the 18th month of treatment. Lean body mass (kilograms) increased linearly throughout the treatment in both sexes (P < 0.01). Mean total cholesterol (TC) values decreased as a result of marked declines in low density lipoprotein cholesterol in both sexes, although statistical significance was detected only in boys (P < 0.01). High density lipoprotein cholesterol (HDLC) and apolipoprotein AI (Apo-AI) rapidly increased only in boys (P < 0.01). Triglyceride, Apo-AII, Apo-B, Apo-CII, Apo-CIII, Apo-E, and lipoprotein(a) showed no significant changes compared with baseline levels. Mean TC/HDLC and Apo-B/Apo-AI ratios decreased during treatment in both sexes, but the difference from baseline was significant only in boys (P < 0.01). After discontinuation of GH treatment, BF increased, and lean body mass decreased in boys (P < 0.01), whereas these variables did not change in girls. TC and low density lipoprotein cholesterol increased in boys within 6 months of discontinuing GH (P < 0.05). Other lipoproteins did not change in either sex, except for lipoprotein(a), which decreased significantly 6 months after the cessation of GH treatment in boys (P < 0.01). The mean TC/HDLC and Apo-B/Apo-AI ratios increased in boys slightly, but insignificantly. We concluded that GH treatment has beneficial effects on body composition and lipid profiles in both boys and girls with GH deficiency, although there are considerable gender differences. These beneficial effects of GH were reversed after the discontinuation of GH treatment, suggesting an important role of GH for GH-deficient children in the maintenance of normal metabolism even after the completion of linear growth.

Growth hormone treatment of short children born small for gestational age.

The administration of growth hormone (GH) for a short period to short children born small for gestational age increases growth velocity. Children receiving 2-3 times the replacement dose gained nearly 2.0 SDS in height over a 3-year treatment period. This treatment is well tolerated, without significant side-effects. Further studies of the growth rate following cessation of GH treatment will reveal whether the gain in height is maintained, and whether the final height prediction is improved.

Effects of human growth hormone in critically ill nonseptic patients

To study the effects of growth hormone administration on insulin-like growth factor I concentration, nitrogen balance, and fuel utilization, and to study its safety in critically ill nonseptic patients. Prospective, randomized, placebo-controlled trial. Medical intensive care unit of a university hospital. Eighteen critically ill nonseptic patients were studied for 8 days after admission. Growth hormone (0.1 mg/kg/day) or placebo was administered as a continuous intravenous infusion on the second, third, and fourth days after admission. The study period was 8 days. Plasma hormone concentrations were measured every 6 hrs and average daily values were calculated. The 24-hr urinary nitrogen and 3-methylhistidine excretion were measured. Indirect calorimetry was used to calculate fuel utilization. Insulin-like growth factor I concentrations increased in the treatment group from subnormal to normal values and remained increased despite discontinuation of growth hormone treatment (p = .02). Nitrogen balance differed between the groups upon admission: growth hormone group (3.9 +/- 4.1 g/day) vs. controls (13.8 +/- 5.4 g/day), but improved with growth hormone. This finding appeared independent of the imbalance between the groups. The 3-methylhistidine excretion was not different between the groups and did not change during growth hormone administration. Free fatty acids and glycerol concentrations increased during growth hormone treatment, but calculated fuel utilization did not change. During growth hormone treatment, insulin concentrations increased, due to the increased administration of insulin necessary for glycemic control. Side effects other than hyperglycemia were not observed. Growth hormone administration in a heterogeneous group of critically ill nonseptic patients resulted in normalization of insulin-like growth factor I levels, even after cessation of growth hormone treatment. Nitrogen balance improved, but this change was transient. Hence, growth hormone affects nitrogen balance, probably partly independent of insulin-like growth factor I.

Growth and carcass composition of pre-pubertal dairy heifers treated with bovine growth hormone

ABSTRACTThe effects of long-term administration of exogenous growth hormone (GH) on growth and carcass composition of pasture-fed, pre-pubertal dairy heifers were examined. Purified bovine GH (specific activity, 0·78 i.u. per mg) was administered daily for 21 weeks (0·6 mg GH per kg M0·75) to one member of each of 12 sets of twins. GH administration resulted in a significantly higher growth rate (0·58 kg/ day) compared with the control group (0·54 kg/day) and produced a heavier carcass (75·6 kg v. 69·5 kg). However, this production gain did not persist when GH treatment ceased. Plasma metabolite concentrations and carcass composition were not affected by GH treatment. GH tended to increase slightly the voluntary intake of freshly cut herbage dry matter (3·5 kg/day v. 3·7 kg/day; P &lt; 0·05), but had no effect on food conversion efficiency. Serum somatomedin levels were not significantly increased by GH during week 13 of treatment. This experiment indicates that pre-pubertal heifers chronically treated with GH will increase their food intake to sustain an increased rate of growth. However, the production gains made over the treatment period were transient and within 5 weeks of the cessation of GH treatment there was no difference in the live weight of the two groups.