John J. Chipman

Growth Hormone plus Childhood Low-Dose Estrogen in Turner's Syndrome

BACKGROUND Short stature and ovarian failure are characteristic features of Turners syndrome. Although recombinant human growth hormone is commonly used to treat the short stature associated with this syndrome, a randomized, placebo-controlled trial is needed to document whether such treatment increases adult height. Furthermore, it is not known whether childhood estrogen replacement combined with growth hormone therapy provides additional benefit. We examined the independent and combined effects of growth hormone and early, ultra-low-dose estrogen on adult height in girls with Turners syndrome. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 149 girls, 5.0 to 12.5 years of age, to four groups: double placebo (placebo injection plus childhood oral placebo, 39 patients), estrogen alone (placebo injection plus childhood oral low-dose estrogen, 40), growth hormone alone (growth hormone injection plus childhood oral placebo, 35), and growth hormone-estrogen (growth hormone injection plus childhood oral low-dose estrogen, 35). The dose of growth hormone was 0.1 mg per kilogram of body weight three times per week. The doses of ethinyl estradiol (or placebo) were adjusted for chronologic age and pubertal status. At the first visit after the age of 12.0 years, patients in all treatment groups received escalating doses of ethinyl estradiol. Growth hormone injections were terminated when adult height was reached. RESULTS The mean standard-deviation scores for adult height, attained at an average age of 17.0±1.0 years, after an average study period of 7.2±2.5 years were -2.81±0.85, -3.39±0.74, -2.29±1.10, and -2.10±1.02 for the double-placebo, estrogen-alone, growth hormone-alone, and growth hormone-estrogen groups, respectively (P<0.001). The overall effect of growth hormone treatment (vs. placebo) on adult height was a 0.78±0.13 increase in the height standard-deviation score (5.0 cm) (P<0.001); adult height was greater in the growth hormone-estrogen group than in the growth hormone-alone group, by 0.32±0.17 standard-deviation score (2.1 cm) (P=0.059), suggesting a modest synergy between childhood low-dose ethinyl estradiol and growth hormone. CONCLUSIONS Our study shows that growth hormone treatment increases adult height in patients with Turners syndrome. In addition, the data suggest that combining childhood ultra-low-dose estrogen with growth hormone may improve growth and provide other potential benefits associated with early initiation of estrogen replacement. (Funded by the National Institute of Child Health and Human Development and Eli Lilly; ClinicalTrials.gov number, NCT00001221.).

Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients.

Context: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. Objective: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. Design and Setting: This was a prospective observational study in the setting of US clinical practices. Patients and Outcome Measures: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. Results: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects. Conclusions: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement.

Effect of Growth Hormone Replacement on BMD in Adult-Onset Growth Hormone Deficiency

To determine if replacement of GH improves BMD in adult‐onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%.

Inhaled Growth Hormone (GH) Compared with Subcutaneous GH in Children with GH Deficiency: Pharmacokinetics, Pharmacodynamics, and Safety

BACKGROUND Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability. OBJECTIVE We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH. DESIGN/METHODS This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods. RESULTS Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen. CONCLUSIONS In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

Regulation of Gonadotropin Secretion in Turner's Syndrome

Abstract To determine the role of body fat in regulating secretion of luteinizing hormone and follicle-stimulating hormone, we measured both at 20-minute intervals for 24 hours in eight children with Turners syndrome. The 24-hour mean luteinizing hormone levels varied from 20.2 to 70.5 mlU per milliliter. Total body weight, total body fat and percentage of body fat showed a significant negative correlation with the 24-hour mean luteinizing hormone concentrations (P<0.01). The 24-hour mean follicle-stimulating hormone concentrations ranged from 60.4 to 229 mlU per milliliter, with a significant negative correlation between total body fat and percentage body fat and the 24-hour mean concentrations (P<0.05). These negative correlations were not mediated by estrogens or androgens. (N Engl J Med 298:1328–1331, 1978)

United States multicenter study of factors predicting the persistence of GH deficiency during the transition period between childhood and adulthood

BackgroundMany patients with childhood-onset growth hormone (GH) deficiency do not fulfill diagnostic criteria for GH deficiency (GHD) after attainment of adult height and may not require long-term GH treatment. Patients with history of idiopathic GHD (IGHD) pose the greatest management dilemma, as data regarding factors predictive of persistent GHD in this group are lacking.ObjectivesThe objective of this study was to assess potential predictors of persistent GHD in a US patient cohort during transition from childhood to adulthood, particularly in patients with history of IGHD.MethodsWe studied 73 US patients with history of childhood-onset GHD screened at 21 US pediatric endocrine centers for a randomized clinical trial of GH replacement after attainment of adult height. The cohort comprised 42 boys/men and 31 girls/women aged14–22 years, who had received ≥1 year of GH treatment and had completed linear growth. The main outcome measures were sensitivity, specificity, positive and negative predictive values (PPV, NPV) of clinical and hormonal factors for persistent GHD (defined a priori in this study as peak GH < 5 μg/L).ResultsFor the cohort as a whole, the best predictors of persistent GHD (100% PPV) were history of organic hypothalamic-pituitary disorder or ≥2 additional pituitary hormone deficiencies (PHD). Best predictors of persistent GHD in patients with childhood history of IGHD were standard deviation scores (SDS) for serum insulin-like growth factor binding protein-3 (IGFBP-3) below -2.0, and for insulin-like growth factor-I (IGF-I) below -5.3 (measured ≥6 weeks after completion of GH treatment; PPV 100% for both), and age <4 years at original diagnosis (PPV 89%). IGF-I above -1.6 SDS had 100% NPV.ConclusionsUS patients with an organic cause of childhood-onset GHD or ≥2 additional PHDs may not require GH stimulation testing to reconfirm GHD after completion of childhood treatment. In contrast, patients with idiopathic childhood-onset GHD almost invariably require retesting, as GHD persists in only a minority (those who were very young at initial diagnosis and those who have subnormal IGFBP-3 or extremely low IGF-I after completion of childhood treatment). Subnormal posttreatment IGF-I (<-2.0 SDS) lacked predictive power for persistent GHD, whereas IGF-I > -1.6 SDS was 100% predictive of GH sufficiency.

Short-term safety of somatropin inhalation powder in adults with mild to moderate asthma.

Systemic therapeutic protein delivery through the lungs could potentially replace delivery by injection, but safety needs to be established in patients with known pulmonary disease. This study determined the short-term safety profile of recombinant human growth hormone (rhGH; somatropin) inhalation therapy in clinically stable adult subjects with mild to moderate asthma and methacholine sensitivity. This randomized, placebo-controlled study had two phases: (1) an escalating 3-dose, 4-day/dosage tolerance phase; and (2) a 14-day, crossover design comparability phase. Noninferiority in maintaining forced expiratory volume in 1 second (FEV(1)) was tested for somatropin inhalation powder (SIP) compared with subcutaneously injected rhGH (Hsc) and inhaled placebo. Lung hyperresponsiveness was assessed by methacholine bronchoprovocative challenge, and adverse events (AEs) were recorded. Eight and 18 subjects enrolled in the first and second phases, respectively. Noninferiority of SIP compared with Hsc and placebo was established for FEV(1) after the first and last doses, and noninferiority of SIP compared with Hsc for methacholine challenge was established after the first dose. Pulmonary uptake and systemic distribution of SIP was confirmed by increased serum insulin-like growth factor I levels. Mild, nonprogressive cough and nasal congestion occurred more commonly with SIP. All other treatment-emergent AEs were mild, similar across active treatment groups, and consistent with rhGH treatment. In clinically stable adults with mild to moderate asthma, no significant changes in pulmonary function or worsening of asthma complaints occurred during SIP treatment. Future studies of SIP may enroll subjects with mild to moderate asthma for longer-term evaluation of safety and efficacy.

Growth Hormone Does Not Impair Carbohydrate Tolerance in Patients with Turner Syndrome |[dagger]| 471

Growth Hormone Does Not Impair Carbohydrate Tolerance in Patients with Turner Syndrome † 471

Factors Influencing Response to Growth Hormone Therapy in Patients with Turner Syndrome † 396

Factors Influencing Response to Growth Hormone Therapy in Patients with Turner Syndrome † 396

REGULATION OF GONADOTROPIN SECRETION IN TURNERʼS SYNDROME

To determine the role of body fat in regulating secretion of luteinizing hormone and follicle-stimulating hormone, the authors measured both at 20 minute intervals for 24 hours in 8 children with Turners syndrome. All 8 patients were short and had no pubertal signs. The range of chronologic age was from 127/12 to 158/12 years. Five of the patients were XO, and 3 were mosaics (2 were XX/XO and one was XX/XXr). No patient had any clinical evidence of an estrogen effect. The 24 hour mean luteinizing hormone concentration varied between 20.2 and 70.5 mIU/ml.; the mean ± S.D. for the 8 patients was 46.3 ± 16.1. The 24 hour mean follicle-stimulating hormone concentration varied between 60.4 and 229 mIU/ml.; the mean ± S.D. for the 8 patients was 146.2 ± 50.9. There was a significant negative correlation between body weight (r = −0.85; P < 0.01), lean body weight (r = −0.75; P < 0.05), surface area (r = −0.83; P < 0.05), body fat (r = −0.88; P < 0.01), percentage body fat (r = −0.84; P < 0.01) and the 24 hour mean luteinizing hormone concentration. There was a significant negative correlation between total body fat (r = −0.77; P < 0.05), percentage of body fat (r = −0.75; P < 0.05) and the 24 hour mean follicle-stimulating hormone concentration. The plasma estradiol concentration was measurable in only 2 patients. With use of the lowest detectable level in the 6 patients whose levels were below the limits of assay sensitivity, the mean ± S.D. plasma estradiol was 13.8 ± 5.6 pg./ml. The mean plasma estrone was 49.5 ±19.1 pg./ml. The 24 hour mean ± S.D. plasma androstenedione, testosterone and dehydroepiandrosterone sulfate were 0.39 ± 0.28, 0.10 ± 0.06 and 1053.8 ± 679.1 ng./ml., respectively. There were no significant correlations between the above estrogens and androgens and the 24 hour mean luteinizing hormone or follicle-stimulating hormone concentrations. In addition, there were no significant correlations between these 24 hour mean estrogen and androgen concentrations and the calculated values for body weight, lean body weight, body fat, percentage of body fat or surface area. In 2 patients with Turners syndrome (XO and XO/XX), the measured values of total body water were 26.2 and 13.2 liters, and the calculated values with the equation of Mellits and Cheek were 26.4 and 13.4 liters, respectively.