Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

Growth hormone treatment does not alter lower limb asymmetry in children with Russell-Silver syndrome

BACKGROUND: Growth hormone (GH) treatment has been proven to have a beneficial effect on growth in children with Russell-Silver syndrome (RSS). METHODS: We describe 7 prepubertal children with RSS and lower limb asymmetry treated with GH for 3 years. RESULTS: There was a significant increase in height without any significant change in the asymmetry. CONCLUSIONS: We conclude that the rapid growth acceleration to GH treatment does not alter the lower limb asymmetry in children with RSS.     

Intrauterine growth retardation and puberty in girls.

Some, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.     

Factors associated with height catch-up and catch-down growth among schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirão Preto (RP), a more developed city, and in São Luís (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score≥0.67 was considered catch-up; a change in z-score≤−0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant''s sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10^th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth.     

Growth hormone response to a bolus injection of 1-44 growth-hormone-releasing hormone in very short children with intrauterine onset of growth failure

The release of growth hormone (GH) during the 120 min following a bolus venous injection of 1-44 GH-releasing hormone (GHRH) 2 micrograms/kg was studied in 52 prepubertal children aged 8.4 +/- 2.1 years, having a nonfamilial growth deficiency of prenatal onset (-3.26 +/- 1.13 SDS at birth, -3.22 +/- 0.88 SDS at the time of study) and a normal response to conventional GH stimulation tests. GH release reached a peak level of 96.1 +/- 60.2 microU/ml, being significantly higher than that found in 68 non-GH-deficient very short children whose growth failure had a postnatal onset, and not significantly correlated with the response to conventional tests. 26 of the 52 intrauterine growth retardation (IUGR) patients were re-tested with GHRH in similar conditions after 6-12 months of daily subcutaneous injections of GH and 2 days without. They reached at the second test a peak plasma GH level of 91.7 +/- 56.1 microU/ml, not different from their response to the first test. These data could be taken into consideration for long-term studies of the clinical effects of GH in IUGR children with persisting severe growth deficiency.     

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.     

Metabolic consequences of growth hormone treatment in paediatric practice

No metabolic side-effects of clinical significance have been reported during a 5-year study of growth hormone (GH) therapy in children with GH deficiency, Turner syndrome, idiopathic short stature or chronic renal insufficiency. In particular, insulin levels increase but remain within the normal range, as do glucose and haemoglobin A(1c). A recent study showed that the effects of growth on insulin sensitivity in prepubertal children with idiopathic short stature represent the changes in carbohydrate tolerance observed during normal adolescence. Thus, GH treatment may lead to prolongation of the physiological state of insulin resistance observed in normal puberty. Insulin levels during the fasting state and 2 h after a standard glucose load showed no further rise after the first 3 years of continuous GH therapy. The hyperinsulinaemia observed during GH therapy may, therefore, amplify the anabolic effects of insulin on protein metabolism during puberty.     

The role of insulin-like growth factor I monitoring in growth hormone-treated children

Growth hormone (GH) therapy has evolved rapidly over the past decade, and continuing research has established a clear role for therapeutic GH in a wide spectrum of disorders, including idiopathic GH deficiency (childhood- and adult-onset), Turner syndrome, Prader-Willi syndrome, small-for-gestational age children with failure of catch-up growth, AIDS-related catabolism, children with chronic renal failure, and idiopathic short stature. Although GH is used therapeutically in a wide variety of conditions, actual guidelines regarding the logistics of GH dosing continue to evolve, with data emerging regarding efficacy and safety. This review proposes a role for insulin-like growth factor I measurement in optimizing GH dosing.     

Non-conventional use of growth hormone: European experience

Results from several centres in Europe using biosynthetic human growth hormone (hGH) for the promotion of growth in a variety of conditions other than classical hGH deficiency were evaluated. Significant increments in growth rates were achieved by daily administration of hGH in doses appropriate for body size without disproportionate skeletal advances in short normals, Turner syndrome, low birth weight, skeletal dysplasia, central precocious puberty (reared with gonadotrophin-releasing hormone analogue) and renal failure.     

Usefulness and limitation of measurement of insulin-like growth factor binding protein-3 (IGFBP-3) for diagnosis of growth hormone deficiency.

To analyze the utility of insulin-like growth factor binding protein-3 (IGFBP-3) radioimmunoassay for diagnosis of growth hormone deficiency (GHD) we measured IGFBP-3 in sera from normal children, short children and patients with GHD. The sensitivity (true positive ratio) of IGFBP-3 for complete GHD (cGHD) was 93%, while the specificity (true negative ratio) for normal short children (NS) was 88%. In contrast, the sensitivity of IGFBP-3 for partial GHD (pGHD) was only 43%. The poor discrimination between patients with pGHD and NS may be the result of their relatively similar GH level, as compared to cGHD, or due to the limitations of GH stimulation tests. The specificity of IGFBP-3 for NS was excellent in children of all ages: less than 10 years old (87%) and older than 10 (88%). However, sensitivity for GHD was good for children less than 10 years old (84%) but poor for children older than 10 (64%). IGFBP-3 may be less sensitive for diagnosing GHD in older children because IGFBP-3 levels may also increase during puberty due to mechanisms independent of the GH-IGF-I axis.     

Effect of chronic clonidine treatment on urinary growth hormone excretion and linear growth in children with short stature

Eleven prepubertal children with short stature were treated with clonidine (0.15 mg/m2 daily) for a period of 1 year. The effect of this drug was evaluated on both clinical (growth velocity, height standard deviation scores for chronological age and bone age) and hormonal (urinary growth hormone excretion and insulin-like growth factor I) parameters. Our study shows that long-term clonidine administration in children with short stature did not result in significant differences in growth velocity, height standard deviation scores for chronological age and bone age, insulin-like growth factor I or in urinary growth hormone excretion.     

Insulin-like growth factors as diagnostic tools in growth hormone deficiency during childhood and adolescence: the KIGS experience

Growth hormone (GH) deficiency in children covers a spectrum of disorders involving an impairment in GH secretion and a clinical syndrome characterized by permanent stunting of growth. Ascertaining impairments in GH secretion directly is complex, especially if GH deficiency (GHD) is isolated and not caused by congenital or acquired pituitary defects or genetic abnormalities. It has been established that the concentrations of GH-dependent peptides, such as insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3), are low in patients with GHD. Their levels are, however, also influenced by a multitude of factors, such as age, gender, height, liver function, nutritional status and other hormones. In addition, the type of complex formed, e.g. either binary or ternary, may influence the measurements of IGFs and their binding proteins. Therefore, levels of IGF-I and IGFBP-3 are generally lower in short children compared with age-matched norms. The reported diagnostic value of sub-normal basal levels of IGF-I and IGFBP-3 is, in terms of sensitivity and specificity, approximately 70%. Thus, definite proof of GHD can only be achieved by means of GH measurements. As the diagnosis of GHD is somewhat unlikely if IGF testing shows normal values, it is clearly advantageous to schedule these tests as part of the initial diagnostic work-up in short children, as their implementation is not only practical but also inexpensive. The Pfizer International Growth Database (KIGS) analysis of IGF-I (n = 2,750) and IGFBP-3 (n = 1,300) levels in children with idiopathic GHD shows that these two parameters are now firmly embedded in diagnostic strategies around the world.     

Human placental transthyretin in fetal growth restriction in combination with preeclampsia and the HELLP syndrome

Fetal growth restriction is a serious, still poorly understood pregnancy-related pathology often associated with preeclampsia. Recent studies speculate on the role of human transthyretin, a carrier protein for thyroxin and retinol binding protein, in the etiology of both pregnancy pathologies. Objective was to investigate the localization and abundance of transthyretin (TTR) in placentas of pregnancies suffering from fetal growth restriction with and without preeclampsia and HELLP. This was a retrospective case control study on human paraffin-embedded placentas from pregnancies with a gestational age at delivery between the 24th and 34th week of gestation. 16 placentas were included in this study, 11 cases and 5 from normotensive pregnancies as controls. Cases were divided into three groups: four from early onset idiopathic intrauterine growth restriction (IUGR), four from early-onset severe preeclampsia (PE), and three from early-onset IUGR with preeclampsia plus HELLP syndrome. Distribution and abundance of TTR were investigated by means of immunohistochemistry. Semi quantitative analysis of TTR staining of placental sections revealed that TTR was mostly expressed in the villous trophoblast covering placental villi. Only weak staining of TTR in villous stroma could be detected. The comparison of placentas revealed that in pure IUGR and severe PE there is a much stronger TTR reactivity compared to controls and cases with IUGR?+?PE?+?HELLP. Concluding, the study showed that TTR is dysregulated in cases of IUGR and severe early onset preeclampsia. Interestingly, TTR expression is not affected in cases with HELLP syndrome that reveal the same staining intensities as age-matched controls.     

Prevalence of severe growth hormone deficiency.

Four hundred and forty-nine short children, who were all over 2-5 standard deviations below the mean height for age, were identified by screening the heights of 48 221 6- to 9-year-old children in three Scottish cities. Most were screened for growth hormone deficiency (GHD). The prevalence of severe GHD in this sample may have been as high as 1 in 4018, much higher than reported. The findings suggest that present referral patterns may account for the delayed or missed diagnosis of the condition in girls or children with less severe short stature.     

The effect of growth hormone therapy on craniofacial growth and dental maturity in children with Down syndrome.

Craniofacial growth was evaluated 3 years after termination of growth hormone (GH) therapy in ten Down syndrome (DS) children. The control group consisted of 16 age-matched children with DS. The treatment started at 6-9 months of age, and the duration was 36 months. There were no statistically significant differences in craniofacial development between DS children treated with GH or DS children not treated. In conclusion, the results of this study indicate that GH therapy for 36 months in children with DS did not change the craniofacial morphology compared to a group of DS children not given GH.     

Intrauterine growth retarded piglet as a model for humans – Studies on the perinatal development of the gut structure and function

The overall acceptance of pig models for human biomedical studies is steadily growing. Results of rodent studies are usually confirmed in pigs before extrapolating them to humans. This applies particularly to gastrointestinal and metabolism research due to similarities between pig and human physiology. In this context, intrauterine growth retarded (IUGR) pig neonate can be regarded as a good model for the better understanding of the IUGR syndrome in humans. In pigs, the induction of IUGR syndrome may include maternal diet intervention, dexamethasone treatment or temporary reduction of blood supply. However, in pigs, like in humans, circa 8% of neonates develop IUGR syndrome spontaneously. Studies on the pig model have shown changes in gut structure, namely a reduced thickness of mucosa and muscle layers, and delayed kinetic of disappearance of vacuolated enterocytes were found in IUGR individuals in comparison with healthy ones. Functional changes include reduced dynamic of gut mucosa rebuilding, decreased activities of main brush border enzymes, and changes in the expression of proteins important for carbohydrate, amino acids, lipid, mineral and vitamin metabolism. Moreover, profiles of intestinal hormones are different in IUGR and non-IUGR piglets. It is suggested that supplementation of the mothers during the gestation and/or the IUGR offspring after birth can help in restoring the development of the gastrointestinal tract. The pig provides presumably the optimal animal model for humans to study gastrointestinal tract structure and function development in IUGR syndrome.     

Septo-optic Dysplasia

Four children are described who had hypoplastic optic nerves, absent septa pellucida, and various types of endocrinological dysfunction. The importance is stressed of recognizing this syndrome and of following up the growth of the patient, because now that human growth hormone is available the short stature of some blind children may be susceptible to treatment.     

Psychosocial adaptation to short stature - an indication for growth hormone therapy?

Although growth hormone does not clearly improve final height in non-growth-hormone-deficient children with short stature, it leads to a temporary acceleration of growth velocity. It is an ongoing discussion whether this effect supports psychosocial adaptation to short stature and therefore could be an indication for growth hormone treatment in children with short stature without growth hormone deficiency. We have reviewed recent literature concerning psychosocial consequences of short stature. Together with own data we can demonstrate that short people regularly adapt well to their height and have a good self-esteem. On the other hand, we focus on the problem that most studies on this subject suffer from methodical problems. A growth-related questionnaire that evaluates subjective and objective perceptions of being short in patients and peers is not at hand. As a consequence, psychosocial problems due to short stature have not been exactly classified yet and therefore do not represent an indication for growth hormone therapy.