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Until recently, human growth hormone was the only endocrine therapy available for promotion of growth and development. Dramatic progress in understanding the secretory and regulatory pathways pertinent to the anabolic steroids has led to multiple pharmacologic approaches. Growth hormone dynamics and its impact on therapy are discussed.
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The growth hormone (GH) pathway is composed of a series of interdependent genes whose products are required for normal growth (Fig 1). The GH pathway genes include ligands (GH and insulin-like growth factor 1 [lGF-1]), transcription factors (prophet of pit 1, or prop 1 and pit 1), agonists and antagonists (growth hormone-releasing hormone [GHRH] and somatostatin), and receptors (GHRH receptor [GHRHR] and the GH receptor [GHR]). These genes are expressed in different organs and tissues, including the hypothalamus, pituitary, liver, and bone. Effective and regulated expression of the growth hormone pathway is essential for growth in stature as well as homeostasis of carbohydrate, protein, and fat metabolism.
Growth disorders are commonly observed in children suffering from chronic inflammatory diseases such as Juvenile Idiopathic Arthritis (JIA) and Inflammatory Bowel Disease (IBD). These disorders range from general growth retardation to local acceleration of growth in the affected limb and are associated with the increased production of pro-inflammatory cytokines. In this article, we review how cytokines influence child growth by exerting a local effect at the level of the growth plate, and through systemic effects throughout the whole body.
In summary, accurate identification of fetal growth disorders remains a difficult clinical challenge. Many diagnostic parameters have been devised to diagnose these conditions, however, no single test alone allows a confident antenatal diagnosis of IUGR or macrosomia to be established. Until new criteria or new methods such as Doppler analysis of umbilical artery flow permit a more accurate prediction of growth disturbances, multiple parameters should be monitored. Evaluation of the amniotic fluid volume, BPD, FL, AC, and EFW should be included in all studies. In high risk cases (unexplained oligohydramnios, previous history of growth retardation, poor nutritional status, abnormal sonographic parameters, maternal obesity, diabetes mellitus, etc.) additional measurements such as the HC/AC ratio and the FL/AC ratio should also be evaluated. Similarly, evaluation of suspected excessive fetal growth requires careful evaluation of AC measurements. Patients with suspected growth disorders should be reevaluated with serial scans at 2 to 3 weeks intervals. Careful monitoring of fetuses with suspected IUGR and macrosomia may decrease much of the morbidity and mortality associated with these conditions.
In juvenile chronic arthritis both general and localized growth disorders are found. The general growth rate is especially impaired in the severe forms of the disease. In addition, delayed puberty with retarded pubertal growth spurt can temporarily result in growth retardation. Long term treatment with high dosage corticosteroids may intensify the growth failure, leading to severe stunting. Local growth disturbances are caused primarily in the area of the affected joints and secondarily as a result of functional disorders. The individual joints react in a specific, age-dependent manner. Growth acceleration and retardation, as well as various deformities of the bone structures, can be observed. Hands, knees and feet present typical examples of different growth disorders. In the toddler the inflammatory growth stimulus predominates first. This leads to accelerated ossification of the wrist and ankle as well as growth increase in knees, fingers and toes. In the further course and in the older child, shortening and growth reduction predominate. Here the premature fusion of the bones observed for example in fingers and toes, but also in the area of the distal part of the ulna, plays an important role. Arthritis can lead to deformities in all the joints. These deformities are more severe in children with early onset of the disease. Secondary growth disorders are caused by minor use of the joints. When wrists or elbows are involved, the entire hand may remain smaller. In the feet the growth impairment is often even more prominent, due to arthritis of the hips, knees or ankles. Both the general and the local growth disorders can be compensated to a large extent if treatment is begun at an early stage and the disease can be brought to remission. It is of great importance to preserve mobility of the joints in view of the interaction between function and growth.
UNLABELLED: To assess the effect of therapeutic doses of growth hormone (GH) on the feeding problems, food intake, body fat and mealtime interactions of children with growth disorders, an age-matched group of 46 children with Turner syndrome (TS) or Silver Russell syndrome (SRS) was examined using questionnaire measures and direct observation. The children's body fat was measured using bio-electrical impedance analysis and skinfold thickness measurements. Children receiving GH consumed significantly more energy, protein, fat and carbohydrate than did the children who were not receiving GH, independent of the extent of the child's feeding problems. Children receiving GH had less body fat than did children who were not receiving GH. Children who were not receiving GH distracted their parents from the mealtime significantly more often and received more negative prompting and coaxing from their parents to eat than did children who were receiving GH. This study provides evidence to support the theory that appetite and intake is determined in part by growth and growth potential. Feeding problems seen in children with growth disorders are partly due to parental attempts to impose control over their child's intake, when their child consumes less than the parent believes to be adequate. CONCLUSION: GH has a significant impact on both the food intake and parent-child interaction at mealtimes of children with SRS and TS.
A computerized screening system for growth disorders is presented. Its aim is to save time and to facilitate the decision of whether a patient with a suspected growth problem should be referred for specialized evaluation. It uses accepted methods and common sense, and has been shown to be effective. A radiography of the hand and wrist, and a completed data sheet (birth date, date of x-ray, height and weight, parental height, and in girls, whether menarche has occurred) are mailed for analysis. Bone age is rated according to Greulich and Pyle, and Tanner et al. by trained technicians, and the results are supervised by a consultant pediatric endocrinologist. The supplied data and bone age values are then processed by a computer, which compares them with normal values, calculates three different height predictions (Bayley and Pinneau, Roche et al., Tanner et al.), as well as "target height" (estimation of genetic potential), and prints an easy-to-read growth curve. Depending on the constellations of height (normal, below 3rd, above 97th percentile), bone age (normal, retarded, advanced in comparison with chronologic age), and height predictions vs. target height (predictions within, below, above target height range), different messages suggesting the most likely diagnostic possibilities are listed on a computer printout.
A specific radioimmunoassay for insulin-like growth factor-binding protein 3 (IGFBP-3), developed against its binding subunit (IGFBP-3 beta), was used to investigate its diagnostic potential for the evaluation of growth disorders. Various factors were found to influence serum IGFBP-3. Most prominent was its considerable age dependence, showing low levels at birth and a peak at puberty. Its dependence on nutrition was obvious from a reduction by 16% after a 3-day fast. Low levels were observed in patients with impaired hepatic function due to biliary atresia, suggesting that the liver may be a major source. In end-stage renal failure, excessively high concentrations were found due to the accumulation of IGFBP-3-related low-molecular-weight forms, suggesting that the kidneys play an important role for clearance. The dependence of serum IGFBP-3 on GH was evident from a significant correlation with total spontaneous nocturnal GH secretion (n = 43; r = 0.62, p less than 0.001). Constant levels over 24 h and a slow response to GH in patients with GH deficiency indicate slow kinetics of variation. Therefore, serum IGFBP-3 appears to reflect the integrated GH secretion over days. In patients with GH deficiency, IGFBP-3 levels were below the 5th percentile of the normal range (133 of 137). In contrast, children with normal-variant short stature (136 of 142) had levels above this limit. Normal IGFBP-3 levels were also found in Turner syndrome and Silver-Russell syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
Current diagnostic standards for growth hormone deficiency were derived from measurement of growth hormone using polyclonal antibody assays. Recently, however, immunoassays using monoclonal antibodies to growth hormone have been commercially introduced. This study compares growth hormone levels obtained with two new monoclonal assays with levels obtained with a standard polyclonal assay. In 20 patients, the polyclonal assay (National Pituitary Agency) measured a mean growth hormone concentration of 14.0 +/- 10 (SD) ng/dl compared with monoclonal assay 1 (Hybritech) measurement of 10.4 +/- 7.2 ng/dl (P less than 0.01) and monoclonal 2 (Wellcome Co.) measurement of 18.9 +/- 9.8 ng/dl (P less than 0.01). The Hybritech monoclonal assay measured lower growth hormone levels than the polyclonal assay in all 20 patients. The Wellcome assay measured higher growth hormone levels than the polyclonal assay in 17 of 20 patients. There is not complete agreement between polyclonal and monoclonal antibody growth hormone assays in their measurement of plasma growth hormone levels. Clinicians using the new monoclonal antibody growth hormone assays will need to carefully develop separate diagnostic criteria for growth hormone deficiency that takes into account the disparity between the polyclonal assays that were used in the development of the current diagnostic standards and the new monoclonal antibody assays.
Pediatric nurse practitioners have an important role in the routine monitoring of growth and the assessment of growth disorders. The development of good history-taking skills and an accurate, repeatable measurement technique are central to the success of growth assessment and evaluation. Numerous causes exist for growth disorders. The pediatric nurse practitioner can be instrumental in identifying these disorders and in making appropriate referral to a pediatric endocrinologist for further evaluation and treatment.
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Inherited disorders of homocysteine metabolism produce accelerated growth and arteriosclerosis with myointimal hyperplasia. The growth of cell cultures from cystathionine synthetase deficient individuals with homocystinuria is characterized by abnormal contact inhibition and production of an aggregated proteoglycan matrix which binds excess sulfate. Homocysteic acid, a precursor of sulfate ester, increases the growth rate of normal guinea pigs. Synthesis of homocysteic acid from homocysteine thiolactone is more rapid in the livers of young animals than adults, and hypophysectomy results in a pattern of homocysteine thiolactone metabolism resembling that in liver of adult animals. Homocysteine thiolactone metabolism differs in guinea pig, an herbivorous species, and in rat, an omnivorous species. Sulfate binding by cultured human cells is slightly increased when homocysteic acid is present in the culture medium. These observations suggest a relationship between homocysteic acid and somatomedin, a serum polypeptide which mediates the action of growth hormone. The growth disorders associated with homocystinuria, including arteriosclerosis and accelerated growth, are believed to result from increased conversion of methionine to homocysteine thiolactone and homocysteic acid.
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Growth hormone (GH) and prolactin (PR) secretion were evaluated in 28 patients who had sleep apnea or narcolepsy but no other primary neurologic or endocrine disorders. Eighty-one percent of subjects with impaired alertness failed to demonstrate serum GH concentrations in excess of 5 ng per milliliter following oral administration of L-DOPA, 500 mg. Diminished GH responses to sleep and intravenous arginine were observed in 57 percent and 44 percent, respectively, of patients tested. Sleep-related PRL release was less than normal in women with narcolepsy, with or without sleep apnea. All patients had at least one abnormality in GH or PRL secretion.
Analysis of GHR and IGF-I coding sequences in 47 children with normal serum levels of GH, low IGF-I and growth disorders generally did not show mutation in the genes studied. Only one boy had a mutation located in the fifth exon of the GHR gene (C-->T in codon 88). This suggests that the growth disorders in this group of children might be due to a defect in a DNA region regulating expression of the GHR and IGF1 genes or genes involved in their regulation.