Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.     

The importance of growth hormone replacement therapy for bone mass in young adults with growth hormone deficiency

Growth hormone (GH) plays an important role in longitudinal bone growth in childhood, accrual of peak bone mass, and bone preservation in adults. GH deficiency (GHD) is associated with reduced bone turnover and decreased bone mineral density (BMD), especially in patients with childhood-onset GHD. GH replacement therapy stimulates bone remodeling and causes an initial decrease in BMD due to bone resorption and expansion of the remodeling space. This is followed by increased bone formation and a significant increase in BMD that continues with prolonged GH therapy. The effect appears to be dose-dependent. GH dose should be individualized based on factors such as age, oral estrogen therapy, and IGF-I levels. Young GH-deficient adults with low BMD measurements by dual-energy X-ray (DEXA) scan should be considered for GH replacement therapy to reduce future fracture risk.     

Insulin-like growth factors I and II in evaluation of growth retardation

Plasma samples from 68 growth hormone (GH)-deficient children (provocative serum GH level less than 7 ng/ml), 44 normal short children, and 197 children with normal height were assayed by specific radioimmunoassays for the somatomedin peptides, insulin-like growth factors (IGF)-I and -II. Eighteen percent of the GH-deficient children had IGF-I levels within the normal range for age, whereas 32% of normal short children had low IGF-I levels. Low IGF-II levels were found in 52% of GH-deficient children, but also in 35% of normal short children. However, only 4% of GH-deficient children had normal plasma levels of both IGF-I and IGF-II. Furthermore, only 0.5% of normal children and 11% of normal short children had low plasma levels of both IGF-I and IGF-II. We conclude that plasma levels of either IGF-I or IGF-II overlap in GH-deficient and normal short children, but that the combination of radioimmunoassays may permit better discrimination among normal, normal short, and GH-deficient children.     

Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone.

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.     

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.     

Transition of childhood-onset growth hormone-deficient patients to adult healthcare

In patients with childhood-onset growth hormone (GH) deficiency who have reached adult height, the transition from pediatric to adult healthcare is an appropriate time for reassessment of GH status. For patients in whom persistent GH deficiency (GHD) is established by appropriate testing, reinstitution of GH therapy or its continuation can improve quality of life, optimize body composition and bone mineral density, as well as reduce cardiovascular risks associated with GHD. Ongoing GH therapy should be individualized with attention paid to changes in serum insulin-like growth factor (IGF)-I concentrations, body composition, and occurrence of adverse effects such as edema and arthralgia. GH deficient patients who discontinue childhood GH replacement therapy and are not restarted as adults should undergo long-term surveillance to detect possible adverse consequences (e.g. reduced bone mineral density) typically associated with interruption of GH treatment.     

Regulation of bone mass by growth hormone

Growth hormone (GH) is a peptide hormone secreted from the pituitary gland under the control of the hypothalamus. It has a many actions in the body, including regulating a number of metabolic pathways. Some, but not all, of its effects are mediated through insulin-like growth factor-I (IGF-I). Both GH and IGF-I play significant roles in the regulation of growth and bone metabolism and hence are regulators of bone mass. Bone mass increases steadily through childhood, peaking in the mid 20s. Subsequently, there is a slow decline that accelerates in late life. During childhood, the accumulation in bone mass is a combination of bone growth and bone remodeling. Bone remodeling is the process of new bone formation by osteoblasts and bone resorption by osteoclasts. GH directly and through IGF-I stimulates osteoblast proliferation and activity, promoting bone formation. It also stimulates osteoclast differentiation and activity, promoting bone resorption. The result is an increase in the overall rate of bone remodeling, with a net effect of bone accumulation. The absence of GH results in a reduced rate of bone remodeling and a gradual loss of bone mineral density. Bone growth primarily occurs at the epiphyseal growth plates and is the result of the proliferation and differentiation of chondrocytes. GH has direct effects on these chondrocytes, but primarily regulates this function through IGF-I, which stimulates the proliferation of and matrix production by these cells. GH deficiency severely limits bone growth and hence the accumulation of bone mass. GH deficiency is not an uncommon complication in oncology and has long-term effects on bone health.     

Pharmacokinetics and pharmacodynamics of recombinant human growth hormone by subcutaneous jet- or needle-injection in patients with growth hormone deficiency

Eighteen growth hormone (GH) deficient children and adolescents (11 6/12–20 9/12 y) participated in a randomized open, two-period (4 weeks) cross-over study to evaluate the pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) administered daily, either by subcutaneous jet-injection or conventional needle-injection. Plasma growth hormone (GH), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), glucose, insulin, HbAlc and serum-free fatty acids (FFA) levels were analysed repeatedly. GH absorption characteristics, expressed as AUC_0-x, Cmax and Tmax ratio (%) jet-injected over needle-injected were similar in both groups. IGF-I and IGFBP-3 plasma levels were identical in both groups. Serum FFA concentrations were comparable after GH administration with either injection device. Surprisingly nocturnal blood glucose decreased to asymptomatic hypoglycaemic levels in all patients. The results of this study showed equal responses concerning absorption and bioavailability of growth hormone administered daily for 4 weeks by either a jet or a needle-injection device in GH-deficient children and adolescents.     

Adult growth hormone deficiency: current trends in diagnosis and dosing

Only approximately 20% of adults with GH deficiency (GHD) have a history of childhood-onset GHD; the remainder acquire GHD in adult life, usually through acquired damage to the pituitary-hypothalamic region. Diagnosis of GHD in adults is more difficult than in children and is made first from the clinical context, reinforced by signs and symptoms, and then confirmed by biochemical testing. The signs and symptoms, however, including altered body composition, reduced energy, and mild depression, are too common to have diagnostic value without a suggestive clinical context. Furthermore, biochemical tests for GH or IGF-I levels are imperfect, characterized by significant false-positive and -negative rates. GH dosing in adults has shifted to an individualized dose-titration approach, in which treatment is begun at a fixed dose and then titrated upward until IGF-I levels normalize, significant side effects develop, or beneficial effects plateau. Generally, women require higher GH doses than do men. Reflecting age-related differences in normal GH secretion, GH doses may be higher in young adults and lower in older patients.     

Growth hormone responsiveness: peak stimulated growth hormone levels and other variables in idiopathic short stature (ISS): data from the National Cooperative Growth Study

HYPOTHESIS: In children with idiopathic short stature (ISS), growth hormone (GH) response to a provocative test will be inversely related to the first year response to hGH and be a variable accounting for a degree of responsiveness. BACKGROUND: Because high levels of GH are a characteristic of GH insensitivity, such as in Laron syndrome, it is possible that a high stimulated GH is associated with a lower first year height velocity among children diagnosed as having ISS. METHODS: We examined the relationship between the peak stimulated GH levels in 3 ISS groups; GH >10 -<25, 25-40, and >40 ng/mL and the first year growth response to rhGH therapy. We also looked at 8 other predictor variables (age, sex, height SDS, height age, body mass index (BMI), bone age, dose, and SDS deficit from target parental height. Multiple regression analysis with the first year height as the dependent variable and peak stimulated GH was the primary endpoint. The predictive value of adding each of the other variables was then assessed. RESULTS: Mean change in height velocity was similar among the three groups, with a maximum difference among the groups of 0.6 cm/yr. There was a small but statistically significant correlation (r=-0.12) between the stimulated GH and first year height velocity. CONCLUSIONS: The small correlation between first year growth response and peak GH is not clinically relevant in defining GH resistance. No cut off level by peak GH could be determined to enhance the usefulness of this measure to predict response. Baseline age was the only clinically significant predictor, R-squared, 6.4%. All other variables contributed less than an additional 2% to the R-squared.     

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children

The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7girls, aged 3.7–13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5–0.7 IU/kg weekly, SC). Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO₄/GFR) were assessed. During therapy with hGH, a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO₄/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO₄/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. Conclusion GH treatment significantly influences mineral metabolism and the measurement of TPO₄/GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children. Received: 16 August 1996 / Accepted: 5 February 1997     

Growth hormone deficiency in patients with sickle cell disease and growth failure

BACKGROUND: Growth disorders are common in children with sickle cell disease (SCD). The etiology for growth disturbances in this population appears to be multifactorial. Recent evidence suggests abnormalities in the growth hormone (GH)/insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) axis may play a role. OBJECTIVE: To measure GH levels through provocative stimulation in a group of patients with SCD with growth failure, and to evaluate response to treatment. PATIENTS AND METHODS: Growth records were reviewed of 79 children with sickle cell hemoglobinopathies to identify children with growth failure. GH levels were measured in patients with SCD with and without growth failure using arginine and L-Dopa as provocative stimulation tests. Treatment with GH was offered to GH-deficient children with SCD and these patients were followed longitudinally over 5 years. RESULTS: Of the 79 patients, 13 (16.5%, all SS) had heights less than -2 SD below the mean or a growth velocity < -2 SD below the mean for age. Seven of the 13 children with growth failure participated in this study. Five patients received GH for 3 or more years and demonstrated significant improvement in their height SDS. One of the two who declined treatment was lost to follow-up and the other had significant worsening of height SDS score. CONCLUSION: GH deficiency may be associated with growth failure in some patients with SCD. These patients may benefit from treatment with GH.     

Empty sella in short children with and without hypothalamic-pituitary abnormalities

A study was conducted on growth hormone (GH) response to oral clonidine (0.15 mg/m²), GH and cortisol responses to i.m. glucagon (0.1 mg/kg), and glucose response to an oral load of glucose (1.75 g/kg). Measurements were made on the circulating concentrations of free thyroxine (FT4), thyroid stimulating hormone (TSH) and different growth parameters and CT sellar images in 25 GH deficient children (Peak GH response to clonidine and glucagon<7 ug/ml), 15 growth retarded children (Ht<5th percentile for age and gender) with sickle cell disease (SCD) and GH deficiency, 30 randomly selected children with normal variant short stature (NVSS) (HtSDS 2SD below the mean for age and gender with normal GH response to stimulation (>10 ug/ml) and 20 age-matched normal children were evaluated. Out of the 25 children with GH deficiency, five had multiple pituitary hormonal deficiency (GH<TSH and/or ACTH. deficiencies), and 20 had isolated GH deficiency. Empty sella, either complete or partial, was detected in 9 out the 20 children with isolated GH deficiency (45%), 4 out of the 5 children with multiple pituitary deficiency (80%), all the children with SCD and GH deficiency (100%), 3 out of the 30 children with NVSS (10%) and in none of the normal children. The insulin-like growth factor-1 (IGF-I) concentrations were significantly lower in the two groups of children with GH deficiency compared to those with NVSS. The height standard deviation scores (HTSDS) were significantly lower and the annual growth velocity was slower in children with idiopathic GH deficiency and empty sella compared to those with NVSS and those with empty sella associated with SCD. The bone age delay (yr) did not differ among the 3 groups of children with short stature. All children with isolated GH deficiency associated with empty sella had normal body mass indices (BMI), while all the children with SCD and empty sella had BMI below the 5th percentile for the corresponding age and gender. None of the children had glucose intolerance. In conclusion, children with growth retardation and abnormal hypothalamic pituitary functions have high incidence of empty sella. However, empty sella is detected in considerable number (10%) of short children with normal hypothalamic pituitary function.     

A practical approach to the diagnosis of growth hormone (GH) deficiency in patients transitioning to adulthood using GH stimulation testing

To establish the diagnosis of adult growth hormone deficiency (GHD), GH-deficient children transitioning to adulthood are evaluated by two separate stimuli 2 or more weeks after ceasing GH therapy. While 20-88% of children diagnosed with idiopathic GHD retest with normal values, those with proven genetic defects in GH production/secretion/bioactivity and patients with panhypopituitarism consistently test deficient. The US Food and Drug Administration (FDA) defines GHD in adults by stimulated peak serum GH concentrations <5 ng/ml if measured by polyclonal radioimmunoassays (RIA) or lower if measured by monoclonal assays. Some investigators define severe GHD by a peak GH concentration <3 ng/ml. Adult responses to arginine and glucagon testing are similar to the responses to insulin tolerance testing; clonidine, pyridostigmine, and galanin cause lesser peaks of GH. Growth hormone-releasing hormone (GHRH) combined with arginine, GH releasing peptide-6 (GHRP-6), or hexarelin leads to higher peak responses than GHRH alone. Thus the choice of testing methods impacts the diagnosis of GHD in transition patients.     

Insulin-like growth factor I actions on steroidogenesis

The best evidence that insulin-like growth factor I (IGF-I) contributes to normal steroidogenesis comes from patients with growth hormone (GH) insensitivity syndrome due to deletion of the GH receptor gene. These patients have severe GH resistance and severe IGF-I insufficiency, and present with markedly delayed puberty without gonadotrophin insufficiency. The same applies to patients with severe isolated GH insufficiency due to GH gene deletion, in whom GH treatment results in normalization of puberty and gonadal steroidogenesis. Delayed sexual maturation is also observed in GH-deficient Snell dwarf mice. These observations strongly suggest that IGF-I plays a role in the endocrine function and differentiation of the gonads.     

Once versus twice daily injections of growth hormone in children with idiopathic short stature

The aim of this study was to compare the growth response of 22 short pre-pubertal children without growth hormone deficiency, treated with a single daily growth hormone injection (group A), to the growth response of 27 similar children, treated with the same daily dose divided into 2 subcutaneous injections per day (group B), for 1 y, in a randomized study. GH treatment significantly promoted growth parameters, height standard deviation score and height velocity standard deviation score in both groups. Serum insulin-like growth factor I was also increased. There were no significant differences in growth response, serum IGF-I levels, or the advance in bone age between the two study groups after 1 y of GH therapy. We conclude that twice daily s.c. growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency.     

Clinical utility of insulin-like growth factor assays

Insulin-like growth I and II (IGF-I and II) mediate many of the peripheral mitogenic actions of growth hormone (GH). The marked dependence of IGF levels on GH adequacy has led to the development of commercial immunoassays for IGF-I (somatomedin-C), and the widespread use of IGF-I levels in the evaluation of short stature. Proper interpretation of IGF-I levels requires consideration of assay methodology, age-related norms, clinical findings, nutritional status, and concurrent hormonal and disease processes. IGF-I levels alone cannot be used to predict stimulated GH response, but may have value in directing the clinical evaluation of a child with short stature. Low IGF-I levels may also be characteristic of a subpopulation of short children with neurosecretory GH deficiency. The role of IGF-II levels in the evaluation of short stature is uncertain, although the combination of low IGF-I and IGF-II levels is more specific for GH deficiency than either value alone. Other clinical applications for IGF assays in pediatrics are also reviewed.     

Serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in severe iodine deficiency

Iodine deficiency is an important public health problem worldwide. It is well known that it has severe consequences such as brain damage, developmental delay, deficits in hearing and learning and lower intellectual attainment. It also has a negative impact on growth. In this study, we aimed to address this issue and we assessed height standard deviation scores of children living in an area of severe iodine deficiency in comparison to those living in a mild iodine deficiency area. Serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), thyroxine (T4), and thyroid stimulating hormone (TSH) were also analyzed to investigate the mechanisms by which iodine depletion leads to growth failure. Pubertal children in a severe iodine deficient SID area had lower height standard deviation scores (HSDS), IGF-I and IGFBP-3 levels than those living in mild iodine deficient MID area. Similar findings could not be elucidated in the prepubertal age group. The major determinants of HSDS were age, IGF-I, IGFBP-3 and TSH. IGF-I and IGFBP-3 were negatively correlated with T4. These findings suggest that iodine deficiency has a negative impact on growth, as well as IGF-I and IGFBP-3 levels. This effect seems to be due to the derangements in thyroid hormone economy arising from iodine depletion. The degree of this impact may be related to the duration of iodine depletion or may be dependent on the developmental stage of the organism at the time of iodine depletion.     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 micrograms/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly (p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs.     

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome

We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome (TS) (mean age 10.7+/-3.6 y) with respect to karyotype, auxological characteristics and growth response to GH treatment (1 IU/kg/wk). None of the patients had spontaneous puberty or had started replacement therapy with estrogens. Thirty-nine patients (48%) had monosomia 45X, 29 (36%) structural abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of GH therapy, each patient underwent an evaluation of mean nocturnal GH concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC of the TS patients did not differ from that of 29 prepubertal GH-deficient girls (GH peaks < 8 microg/l after pharmacological tests) and both groups were lower (p < 0.0001 and p < 0.0005, respectively) than MGHCs of 27 short normal girls (GH peak > 8 microg/l). MGHC of the patients with TS was negatively correlated (p < 0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the TS patients with BWE < 20% was significantly higher (p < 0.02) than that of the TS patients with BWE > 20%, but again did not differ from that of the GH-deficient patients and was lower (p < 0.001) than that of the short normal girls. MGHC did not significantly differ between the 3 groups subdivided according to karyotype. Forty-four percent of the TS patients showed GH responses to pharmacological tests < 8 microg/l. Height velocity SDS at first and second year of therapy was not influenced by MGHC levels, chronological or bone age, target height or BWE. In conclusion, spontaneous secretion in our patients with TS was lower than that of the short normal prepubertal girls and did not differ from that of GH-deficient subjects, even if we excluded overweight patients. The level of GH secretion was unable to predict GH response to treatment.