Cessation Of Growth Hormone Therapy 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.

Reduced Cochlear Implant Performance After the Use of Growth Hormone With Regain of Function After Cessation of Growth Hormone Therapy

To assess whether recombinant growth factor (hGH) therapy has an effect on cochlear implant (CI) performance. Two pediatric CI recipients (S1, S2) who underwent treatment with hGH for short stature were identified for review. S1 has bilateral labyrinthine dysplasia and received implants at ages 10 months (right) and 4 years 3 months (left). S2 was diagnosed with severe to progressive sensorineural hearing loss bilaterally and received a CI at age 9 years 10 months (left). Case series. Cochlear implant, hGH, and speech perception data were collected. Phonetically Balanced Kindergarten (PBK) and Consonant Nucleus Consonant (CNC) word recognition scores were reviewed to assess auditory perception. Electrode impedances, threshold levels, and comfort levels were also reviewed. After 4 months of hGH, word recognition scores for S1 were observed to decrease from 90 to 72% (right) and were stable at 40% (left). Despite troubleshooting, performance continued to decline bilaterally to 52% (right) and 28% (left), and the decision was made to discontinue hGH. One month after cessation of hGH, word recognition scores began improving to 74% (right) and 68% (left). Word recognition scores for S2 were observed to have decreased from 92% the previous year to 82% after taking hGH for 2 months. Given both our previous experience with S1 and discussions with S2's parents, hGH was discontinued after 10 months of therapy. Two months after cessation of hGH, S2's word recognition had improved to 86% (left). Our case studies illustrate that implanted children undergoing treatment with hGH may experience a decrease in speech perception, which recovers after the cessation of treatment. Since hGH use has become more prevalent in recent years, it is important to inquire whether children undergoing, or who have undergone, implantation are receiving hGH so that they may be appropriately monitored.

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.

Growth Hormone (GH) Secretion in Patients with Childhood-Onset GH Deficiency: Retesting after One Year of Therapy and at Final Height

Background: Recent studies have shown that many patients treated with growth hormone (GH) during childhood because of idiopathic GH deficiency (GHD) are no longer GH deficient when retested after cessation of GH therapy when final height is achieved. These patients are labelled as transient GHD. We hypothesized that normalization of GH secretion in transient GHD could occur earlier during the course of GH treatment, which could allow earlier cessation of GH treatment. Methods: In a retrospective study, GH secretion was re-evaluated after cessation of GH treatment at final height in 43 patients diagnosed during childhood as idiopathic GHD (10 with multiple pituitary hormonal deficiencies (MPHD) and 33 with isolated GHD (IsGHD)). In a prospective study, GH secretion was re-assessed after interruption of GH treatment given for 1 year in 18 children with idiopathic GHD (2 MPHD, 16 IsGHD). GH secretion was evaluated by glucagon or insulin stimulation tests. Results: In the retrospective study, all the 10 patients with MPHD and 64% of the 33 patients with IsGHD were still deficient at re-evaluation using the paediatric criteria to define GHD (GH peak <10 ng/ml at provocative test). The proportion of persisting deficiency was greater in patients with complete IsGHD (86%, 12/14 patients) than in patients with partial IsGHD (47%, 9/19 patients). With the criteria proposed in adulthood (GH peak <3 ng/ml), all the 10 patients with MPHD were still considered to be deficient. In contrast, only 15% (5/33 patients) with IsGHD had a maximal GH value <3 ng/ml (36% of the 14 patients with complete IsGHD and none of the 19 patients with partial IsGHD). In the prospective study, after interruption of GH therapy given for 1 year, the 2 patients with MPHD were still GHD at re-evaluation and they resumed GH treatment. Among the 16 patients with IsGHD, 13 (81%) were still deficient (peak response <10 ng/ml) after 1 year. Two of the 3 patients in whom GHD was not confirmed at retesting after 1 year GH showed again a deficient response at second retesting. Conclusions: Although many patients diagnosed with IsGHD during childhood have a normalized GH secretory capacity when retested during adulthood, early retesting after interruption of GH treatment given for 1 year during childhood does not enable to determine if GH therapy has to be discontinued before cessation of growth.

Treatment of Juvenile Rheumatoid Arthritis with Growth Hormone

Severe growth retardation and profoundly altered body composition are observed in children with juvenile chronic arthritis receiving glucocorticoids. This study assessed the effects of growth hormone (GH) on height velocity, body composition and bone density. Fourteen patients were treated with GH (1.4 U/kg/week) for 1 year and then studied for a 2nd year off GH. The treatment increased insulin-like growth factor 1 and insulin-like growth factor binding protein 3 plasma levels. All patients showed an increase in height velocity. Lean body mass increased by 12%. After the cessation of GH therapy, height velocity fell to pretreatment values, and weight and fat mass increased markedly. Bone formation and resorption markers significantly increased during treatment and returned to pretreatment values after discontinuation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.

Sleep apnea in patients receiving growth hormone.

Among 145 patients treated with recombinant human growth hormone (GH), four developed sleep apnea (two obstructive, two mixed) associated with tonsillar and adenoidal hypertrophy in three. These four patients had no local risk factors predisposing to upper airway obstruction (i.e., frequent pharyngitis or sinusitis). Clinical and/or polysomnographic features of sleep apnea improved following cessation of GH therapy in one patient, and following tonsillectomy and adenoidectomy in all patients. The present observations indicate that, albeit rarely, obstructive and/or central sleep apnea may occur in children treated with GH. Polysomnography should be considered if symptoms of snoring, interrupted sleep, daytime somnolence-particularly if associated with tonsillar hypertrophy-appear in children during GH therapy.

Safety of human growth hormone therapy: Current topics

Current data on patients treated with human growth hormone (GH) were analyzed for the following safety topics. New leukemia . Thirteen of 46 new cases of leukemia were in non-Japanese patients without risk factors for leukemia (compared with at least 13 new cases expected). A possible increased occurrence of leukemia with GH treatment appears to be limited to patients with risk factors. Nonleukemic extracranial neoplasms. The number of cases reported (10) does not differ significantly from the number expected. Acute pancreatitis . In five of the seven cases reported risk factors (renal failure, valproic acid use, insulin-dependent diabetes mellitus) were present. The available data do not indicate a clear cause-and-effect relation between GH therapy and pancreatitis. Prepubertal gynecomastia . Of 15 possible cases, two were pubertal, eight resolved or improved with continued GH therapy, and two resolved with the cessation of GH therapy. An effect of GH treatment on prepubertal gynecomastia remains unknown. Scoliosis . Scoliosis is reported in fewer than 1% of the patients in the National Cooperative Growth Study (general-population prevalence, 1.5% to 3%). Curvature progression can occur during growth acceleration, and a causal association with GH treatment is not substantiated. Pigmented nevi . Nevi growth may be increased with GH treatment. Biopsies have detected no neoplasia or premalignant nevi transformations. (J P EDIATR 1996;128:S8-13)

Growth hormone measurements versus auxology in treatment decisions: The Australian experience

Growth hormone (GH) therapy is regulated in Australia by an expert national government committee. A national database (OZGROW) enables regular audits and rational guideline revisions. In 1988 the guidelines were revised to allow eligibility on auxologic criteria alone because of difficulties in diagnosing GH deficiency (GHD) and GH responses in non–GH-deficient children. Initial entry criteria were height less than the 3rd percentile and growth velocity less than the 25th percentile for bone age. Growth hormone testing was continued in most children. More than 3100 children have been treated since 1988 (35% with GHD, 12.5% with Turner syndrome, and 52% with other non-GHDs). Five-year responses (change in height SD scores) were best in the group with complete GHD (+2) (which received the lowest dose of GH) and similar in other groups, including those with partial GHD (+1.5). The increase in final height is 4 to 6 cm in subjects with Turner syndrome. This data is not yet available for subjects with other non-GHDs. In 1994 the guidelines were revised to restrict use of GH therapy to subjects with height less than the 1st percentile, and cessation of GH therapy was brought forward to bone age 13.5 years for girls and 15 years for boys. Subjects with maturational delay were excluded because of the finding that in the presence of significant bone age delay height prognosis was good. New patient accruals have decreased since 1992, from 100/yr to less than 50/yr. Expenditures have also fallen, from $31 to $16 in 1994-95, because of reduced patient numbers and GH pricing. Australian use of GH is 68.7% that of the United States and 42.4% that of Sweden and is in the mid-range internationally. In conclusion, an auxology-based GH program coupled with a comprehensive national database enables rational and economic use of GH in short children. (J P EDIATR 1996;128:S47-51)

Leukemia in GH Deficient Children

Leukemia Study Group of the Foundation for Growth Science, Japan, Epidemiology Division, National Cancer Center, Tokyo (SW SM), Hemato-oncology Division, National Children's Hospital (YT), Department of Pediatrics, Shinshu University, Nagano (AK) and Department of Pediatrics, Kyoto University, Kyoto (CY, MK), Japan The incidence of leukemia, exduding malignant histiocytosis, among growth hormone (GH) users has reached 13 cases in Japan. These consist of six with acute myeloid leukemia (AML), five with acute lymphocytic leukemia (ALL) and two with chronic myeloid leukemia (CML). In nine of these patients the leukemia was idiopathic, but the other three had underlying malignant decease and one had Fanconi's anemia. Leukemia developed during GH treatment in eight patients and after cessation of GH therapy in three. The longest interval between cessation of GH therapy and the onset of leukemia was 10 years. One patient with AML was considered to be already at the preleukemic stage when GH was started. Recently, two new leukemia cases (AML and CML) in GH deficient children who had not received GH have been reported. Analysis of these cases suggests that both high and low GH levels are risk factors for leukemia.

Preservation of Physiological Growth Hormone (GH) Secretion in Idiopathic Short Stature after Recombinant GH Therapy*

This study was undertaken to assess the recovery of spontaneous GH secretion 48 h after the cessation of GH therapy in children with idiopathic short stature treated with recombinant DNA-generated human GH (rhGH-M). Eleven prepubertal children with GH responses of 10.0 ng/mL or more after provocation were divided into therapeutic (n = 7) and control (n = 4) groups. GH was sampled every 20 min for 24 h in six treated and three control patients. One treated and one control patient had 12-h overnight studies because of their weight. The sampling studies were carried out before GH therapy was initiated and 48 h after rhGH was discontinued after 12 months of therapy. Three patients in the treated group also underwent a 24-h study at the 6 month time point. The treated group started treatment with rhGH (0.1 mg/kg), given three times a week. The results showed that pre- and posttreatment GH secretory profiles were comparable with respect to the number of peaks, mean concentrations, peak amplitude, and secretory rate. At the 6 month point, the mean GH and peak GH amplitude (n = 3) were greater than the means of the treatment group (n = 7) at the 0 and 12 month points, but the difference was not statistically significant. Somatomedin-C rose in the treated group from 0.42 +/- 0.1 to 1.25 +/- 0.3 U/mL (mean +/- SD; P less than 0.01). In the control group it rose from 0.56 +/- 0.1 to 1.16 +/- 0.8 U/mL (mean +/- SD; P greater than 0.05) because one patient entered puberty in the 12-month period of observation; his somatomedin-C level rose from 0.72 to 2.5 U/mL. We conclude that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH. These data show that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH and provide evidence for the resilience of the GH secretory system in the growing child.