J.-C. Souberbielle

Hormonal Factors Influencing Weight and Growth Pattern in Craniopharyngioma

Patients operated on for craniopharyngioma frequently suffer from hyperphagia and are obese, but their statural growth is normal despite growth hormone (GH) deficiency. We have evaluated the hormonal factors influencing changes in weight and growth in 17 children before and 1, 3–6, 12, and/or 24 months after surgical resection of a craniopharyngioma performed at 7.7 ± (SE) 1 years of age. Of these, 15 patients had a GH deficiency before surgery, and all had complete pituitary deficiency after it. The plasma fasting insulin concentrations before surgery were positively correlated with body mass index (BMI, kg/m2; p < 0.05), plasma insulin-like growth factors (IGFI, p = 0.03, and IGFII, p = 0.04), and leptin (p = 0.03). They increased significantly 1 month after surgery and continued to increase thereafter, whereas leptin increased significantly only 3–6 months after surgery, paralleling changes in BMI. The plasma fasting insulin concentrations before surgery were also positively correlated with the weight changes (12.3 ± 2.3 kg, p < 0.01) during the 12 months after surgery, but not with changes in BMI SDS (3.1 ± 0.5, p = 0.07). Both expressions of weight change were correlated with the concomitant growth rates (4.8 ± 0.7 cm, p < 0.01). IGFI was above the 10th percentile for children with idiopathic short stature in 10 of 15 patients with craniopharyngioma-induced GH deficiency and IGF-binding protein 3 in 14 of 15 patients. Craniopharyngioma itself modified the control of insulin secretion, and surgery increased the insulin secretion which continued in the same way in a given patient after surgery. The increased insulin secretion in turn increases weight and keeps IGFI nearly normal. This may explain the normal growth rate despite the complete lack of GH.

Growth after bone marrow transplantation in young children conditioned with chemotherapy alone

Short stature is a potential side-effect of BMT, brought about by the conditioning protocol and/or the complications of BMT. This study evaluates the effects of conditioning by chemotherapy, and BMT complications on growth. Thirty children conditioned for BMT by chemotherapy alone (cyclophosphamide and busulfan) were classified according to the occurrence of serious or prolonged complications after BMT: group 1 (n = 12) had no complication, while group 2 (n = 18) did. Fifteen of them were severely growth retarded (⩽ −2 s.d.) at BMT, because of their initial disease. At the time of BMT, the two groups had similar ages (1.0 ± 0.2, s.e.m. year, in group 1 and 1.7 ± 0.5 year in group 2), height (−1.7 ± 0.5; −1.8 ± 0.3 s.d.) and plasma insulin-like growth factor I (IGFI) levels (0.3 ± 0.1 U/ml in both). Group 1 grew significantly and their plasma IGFI increased but group 2 did not, as assessed 2 years post-BMT. We conclude that conditioning with chemotherapy alone does not prevent the catch-up growth induced by BMT in young children; the lack of catch-up growth is due to complications occurring after BMT, and the change in plasma IGFI suggests that complications of BMT prevent any increase in plasma IGFI, and thereby catch-up growth.

Effects on Growth and Metabolism of Growth Hormone Treatment for 3 Years in 36 Children with Prader-Willi Syndrome

Background/Aims: Prader-Willi syndrome (PWS) is a complex genetic disorder whose many manifestations include obesity and short stature. Diabetes, osteoporosis, and scoliosis are common. We evaluated the effects of human growth hormone (hGH). Methods: A prospective cohort study of 36 children (1–15 years of age) with genetically confir med PWS who were given hGH (mean dose 0.033 ± 0.006 mg/kg/day) for 36 months. At baseline and once yearly, we evaluated growth, insulin-like growth factor-1 (IGF-1), body composition, bone mineral density (BMD), glucose tolerance, serum lipids, and spinal radiographs. Results: Height gain over the 3-year period was 1.2 SD score. Lean body mass increased significantly during each treatment year. Total body fat decreased by 5.42 and 1.17% in the 1st and 2nd years, respectively. BMD remained unchanged during therapy. IGF-1 and homeostasis model assessment index of insulin resistance increased, and glucose intolerance was found in 22.7% of patients at baseline and 0% at 3 years. None of the patients had diabetes. Their lipid profile improved. Scoliosis was present in 27.8% of the patients at baseline and 47.2% at 3 years. Conclusion: GH treatment in children with PWS has multiple beneficial effects on growth and body composition. Tolerance is good, with an improvement in glucose metabolism, although IGF-1 levels and insulin resistance parameters should be monitored closely. The high rate of scoliosis warrants monitoring by a pediatric orthopedic surgeon.

Effect of Short-Term Testosterone Treatment on Leptin Concentrations in Boys with Pubertal Delay

Testosterone administration increases growth hormone (GH) secretion and decreases the plasma leptin concentration in men. We evaluated the effect of increased GH secretion due to short-term testosterone treatment on leptin concentrations. Ten boys aged 14.8 ± 0.2 (mean ± SE) years with transient GH deficiency caused by pubertal delay were evaluated before and after (3 months) 4 intramuscular injections of 100 mg testosterone heptylate, given at 15-day intervals. The leptin concentration decreased from 5.4 ± 1.3 to 3.6 ± 1.1 μg/l (p < 0.001), despite a weight gain of 3.4 ± 0.5 kg. There were significant increases in body mass index (BMI), from –0.2 ± 0.5 to 0.2 ± 0.5 SD, p < 0.005, in GH peak after stimulation test, from 6.3 ± 0.5 to 21.7 ± 2.9 μg/l, p < 0.0003, in plasma testosterone, from 0.6 ± 0.1 to 6.5 ± 1.3 μg/l, p < 0.001, in insulin-like growth factor-I (IGF-I), from 152 ± 21 to 330 ± 30 μg/l, p < 0.0001, and in IGF-binding protein-3 (IGFBP-3), from 4.2 ± 0.5 to 5.4 ± 0.4 mg/l, p < 0.01. But there were no changes in blood glucose (4.7 ± 0.1 and 4.8 ± 0.1 mmol/l), or plasma fasting insulin (9.0 ± 1.2 and 8.1 ± 1.3 mIU/l). The leptin concentrations were positively correlated with the BMI before (p < 0.03) and after (p < 0.04) testosterone, but not with the GH peak after stimulation, or with plasma testosterone, IGF-I or IGFBP-3. The leptin and insulin concentrations after testosterone treatment were positively correlated (p < 0.04). Thus, short-term testosterone treatment of boys with pubertal delay decreases their leptin concentrations. The lack of correlation with GH secretion or with its changes, despite the dramatic increase in GH secretion, and the lack of change in insulin are additional features suggesting that testosterone increases the leptin concentration mainly by an effect on adipose tissue.

Assessing Short-Statured Children for Growth Hormone Deficiency

Aim: To optimize the workup of short-statured children by defining the most appropriate tools for diagnosing growth hormone (GH) deficiency. Methods: Patients were assigned to prepubertal (n = 113) or pubertal (n = 112, including 25 boys primed with testosterone) age groups. Mean plasma GH concentration during sleep, GH peak after provocative test, and insulin-like growth factor I (IGF-I) were measured in a single evaluation. Results: The mean GH concentration during sleep was more often normal (n = 155) than the GH peak after provocative tests (n = 105) or the IGF-I concentration (n = 88). Prepubertal patients with a normal body mass index (BMI) had mean GH concentrations during sleep that correlated positively with height, growth rate, GH peak after provocative tests, and IGF-I (p < 0.0005 for all) and negatively with the difference between target and patient heights (p = 0.01) and BMI (p < 0.05). Pubertal patients with a normal BMI had a mean GH concentration during sleep that correlated positively with GH after provocative tests (p < 0.0001) and IGF-I (p < 0.005). Mean GH concentration during sleep and IGF-I concentration for boys primed with testosterone were more often normal (n = 23) than the GH peak after provocative tests (n = 14). All 9 patients with pituitary stalk interruption had low IGF-I concentrations; 1 patient had a normal GH peak after provocative test, and 2 patients had normal mean GH concentrations during sleep. Conclusions: Measuring the GH concentration during sleep and priming boys with pubertal delay can help to exclude idiopathic GH deficiency. Magnetic resonance imaging is needed to exclude anatomic abnormalities when GH and/or IGF-I concentrations are low.

Growth Hormone Deficiency: Permanence and Diagnosis in Young Adults

Objective: To optimize the tools for diagnosing idiopathic growth hormone (GH) deficiency. Methods: We compared the data of 43 young adults treated for GH deficiency before and after GH treatment and puberty. Those with organic lesions were assigned to group 1 (n = 9), those with certain GH deficiency (n = 11) to group 2 and those with no criterion of certitude of GH deficiency to group 3 (n = 23). Results: Group 1 patients: the GH peaks at first [1.5 ± (SE) 0.4 µg/l] and second (1.9 ± 0.7 µg/l) evaluations before treatment were similar to those at the third evaluation (1.2 ± 0.8 µg/l) after treatment. Group 2 patients: they had similar peaks (2.6 ± 0.8, 2.9 ± 0.5 and 5.5 ± 1.4 µg/l). Group 3 patients: the peaks increased from 4.9 ± 0.4 and 4.8 ± 0.4 to 18.4 ± 2.3 µg/l (p < 0.0001); 87% had a GH peak >10 µg/l at this evaluation. The plasma insulin-like growth factor 1 was initially below –2 z-score in 12/13 of these patients and similarly low in 4/17 patients at the third evaluation. The growth rates of the three groups before and their increase during the 1st year of treatment were similar. Conclusion: Almost all patients with GH deficiency before puberty without criteria of certitude had a normal GH peak after puberty. Some of these patients probably had a transiently low GH secretion.

Hypothalamic-pituitary function and growth in children with intracranial lesions

Abstract Intracranial lesions may affect hypothalamic-pituitary (HP) function and growth in several ways, depending on the location of the lesion within this area, the presence or absence of secondary hydrocephalus, and/or treatment of the lesion by surgery and/or radiotherapy. The lesion may cause a deficiency of HP hormones or, conversely, activation of the HP-gonadal axis leading to precocious puberty. Growth hormone (GH) deficiency is the most frequent endocrine abnormality that results from the lesions of the HP area. There has been progress in diagnosis, patterns of replacement therapy and the administration of biosynthetic GH in association with gonadotropin-releasing hormone analogues in precocious puberty. The major problem in these patients is the dramatic increase in their weight, which frequently occurs after surgery and increases their psychosocial and physical disabilities. It may be due to the hyperinsulinism caused by the lesion. This hyperinsulinism may be the factor that replaces GH in stimulating growth factor production and leads to normal growth in some of the patients.

Extreme Short Stature after Intrauterine Growth Retardation: Factors Associated with Lack of Catch-Up Growth

The factors associated with lack of catch-up growth after intrauterine growth retardation (IUGR) are unknown. Objective: To identify these factors by analyzing the clinical features and growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. Methods: 95 patients with height <–3 SD after IUGR were assigned to group 1 without (n = 50) or group 2 with (n = 45) malformations. Twenty-one in group 1 and 19 in group 2 were treated with GH. Results: They were seen at 5.3 ± 0.5 and 4 ± 0.5 year (p = 0.02) with heights at –3.4 ± 0.1 and –3.9 ± 0.2 SD (p = 0.03). Group 1 differed from group 2 in having a lower frequency of consanguinity (2 vs. 28.9%, p < 0.001), and higher frequencies of target heights (26.5 vs. 6.7%, p = 0.02) and mothers’ heights (34.7 vs. 8.9%, p < 0.01) <–2 SD, multiparity (26 vs. 8.9%, p < 0.05), prematurity (36 vs. 15.5%, p < 0.05) and cesarean section birth (42 vs. 17.8%, p = 0.01). The GH-IGF-I axis data and the height increases after 3 years of GH treatment (1.6 ± 0.2 in group 1 and 1.1 ± 0.3 SD in group 2) were similar. Conclusion: The short height of the parents, particularly of the mother, is associated with factors limiting the catch-up growth after IUGR of children without malformations, while the high frequency of consanguinity in those with malformations suggests that transmitted fetal factors affect organogenesis or development.

Extremely Short Stature: Influence of Each Parent’s Height on Clinical-Biological Features

Idiopathic extremely short stature probably has several causes. Objective: To evaluate the influence of each parent’s height on clinical-biological features. Methods: 57 patients without intrauterine growth retardation seen at 7.9 ± 0.4 years for height ≤–3 SD were classified according to the difference between their target height and actual height: <2 SD in familial short stature (FSS, n = 28) and >2 SD in non-FSS (n = 29). Results: Height decreased from –0.5 ± 0.1 SD at birth to –2 ± 0.2 SD at 1 year and –2.7 ± 0.1 SD at 3 years, but the changes in the two groups were similar. FSS children were shorter than non-FSS children both at birth (p = 0.03) and as adults after growth hormone (GH) treatment (p < 0.05), but their plasma insulin-like growth factor I concentrations and GH peaks were similar. The FSS children fathers’ heights were more frequently below –2 SD (64%) than the mothers’ heights (35%) and were correlated with height at first evaluation (p < 0.05). For the whole population, the mothers’ heights were correlated with birth weight (p < 0.05) and with height at first evaluation (p < 0.03). Conclusion: This study confirms the influence of the mother’s height on birth weight and shows how of the father’s height influences idiopathic extremely short stature.

Factors Influencing the Growth Hormone Response to Growth Hormone-Releasing Hormone in Children with Idiopathic Growth Hormone Deficiency

Objective: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. Methods: 28 patients aged 4.9 ± 0.7 years with certain GH deficiency were given GHRH (2 µg/kg). Results: The GH peak after GHRH was correlated negatively with age at evaluation (r = –0.37, p < 0.05) and body mass index (r = –0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. Conclusion: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.