Growth hormone treatment of short stature. State-of-the-art 1989.
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Adult↗
Biomedical subjects
M B Ranke
Publications and source records attributed to M B Ranke.
Adult height in children with constitutional short stature.
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Adult↗
Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I.
The insulin-like growth factors (IGF)-I and -II are bound to specific carrier proteins in the circulation. For investigation of their physiological role, the acid-stable subunit of the major binding protein (SmBP) was isolated from human plasma Cohn fraction IV. Its effect on the mitogenic activity of IGF-I was studied with baby hamster kidney fibroblasts (BHK-21) and human skin fibroblasts. While free IGF-I had no effect on thymidine incorporation into DNA with BHK-21 cells and only a moderate effect with human fibroblasts under standard conditions, DNA synthesis was significantly enhanced with both cell lines if IGF-I was complexed with SmBP before the experiment. The enhancement was optimal at an approximately equimolar ratio of both peptides. In contrast to experiments in which large concentrations of IGF-I were added at the beginning, repeated addition of small quantities of free IGF-I at hourly intervals clearly stimulated DNA synthesis in BHK-21 cells. Binding studies with radiolabeled SmBP revealed no evidence for direct interaction with either cell line. It is concluded that SmBP acts as a reservoir, releasing continuously low amounts of IGF-I and thereby creating a steady state situation of receptor occupancy, which appears to be a better mitogenic stimulus than temporary large concentrations of IGF-I.
Blood Proteins↗
Influence of allogeneic bone marrow transplantation on the endocrine system in children.
With increasing survival rates of children grafted for different malignancies concerns about the longterm side effects of this treatment are growing. Therefore, investigations on the function of endocrine systems were conducted in a total 28 patients grafted for various reasons: ALL (N = 18), AML (N = 1), SAA (N = 3), CML(N = 4), neuroblastoma (N = 2). The results can be summarized as follows: 1. The extent of hormonal derangements is primarily dependent on the extent of irradiation prior to BMT. Integrity of hormonal systems was found in cases without irradiation (SAA) or if TBI did not exceed 3 Gy. 2. Primary hypogonadism was present in 18 patients. 3. Primary hypothyroidism was present in 2 patients. 4. Growth impairment was observed in 8 patients. In four of these cases growth hormone deficiency was the cause. In four other cases with graft-versus-host-disease and hepatic involvement SmC/IGF I levels were severely diminished. The data suggest that in most cases BMT itself has relatively few negative effects on the endocrine regulatory system. However, more detailed investigations before and after BMT will be needed to further validate these observations.
Anemia, Aplastic↗
Noonan syndrome: growth and clinical manifestations in 144 cases.
We have analysed growth and the major clinical manifestations of 144 patients (89 males, 55 females) with Noonan syndrome from two West German centres. Size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd per centile until puberty, but decreased transiently due to an approximately 2 year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the 2nd decade of life. The mean adult height was found to be (n = 20) 162.5 cm in males and (n = 13) 152.7 cm in females, respectively. Smoothed means and standard deviations for height were derived. These data may be used for the statistical evaluation of height of Noonan syndrome patients. Except for mental retardation and microcephaly, which are more frequent in males, the relative frequencies of minor anomalies and malformations were found to be similar in both sexes. The characteristic non-cyanotic heart defects in the Noonan syndrome do not appear to have a major influence on growth. The auxological data were compared with those in the Ullrich-Turner syndrome.
Adolescent↗
Spontaneous growth in Turner's syndrome.
Growth in Turner's syndrome can be divided into four phases: intrauterine growth is slightly retarded, normal growth occurs up to a bone age of about 3 years, with a tendency to compensate for the loss in growth during intrauterine life, stunting of growth is severe during childhood, after a bone age of about 10 years - the time when puberty normally starts - the growth phase is prolonged, but total height gain is not essentially reduced. Based on a study of 150 patients with Turner's syndrome whose spontaneous growth was observed, standards of height and height velocity (means and SDs) were calculated to allow mathematical analysis of the spontaneous growth and growth during treatment in these patients. The auxological characteristics in Turner's syndrome do not support the assumption that GH deficiency plays a primary role in the pathogenesis of the growth disorder.
Adolescent↗
A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess IGF-I.
A specific antiserum for human IGF-II has been produced by immunizing rabbits against the synthetic peptide IGF-II(33-40). With this antiserum and IGF-II as tracer a radioimmunoassay for IGF-II has been developed. Cross-reactivity with IGF-I was 0.05% and half-maximal displacement occurred at 2.5 micrograms IGF-II per 1. It was demonstrated that residual IGF-binding protein (IGF-BP) in acid-ethanol extracts interferes with IGF-II measurements and may produce erroneously high values. This interference could be completely blocked by excess IGF-I (25 ng per tube). Utilizing this method IGF-II was measured in subjects at various developmental stages. In newborns, the mean serum level was 237 micrograms/l (N = 56) with a range of 132-430 micrograms/l (5- and 95-percentile, respectively). During the first year of life a considerable increase occurred. Thereafter IGF-II increased only slightly with age from 520 micrograms/l (range 368-735) to 647 micrograms/l (range 507-823) in adults. In patients with growth hormone deficiency (N = 57) IGF-II levels were significantly (P less than 0.001) lower than in controls (mean 261 micrograms/l, range 126-542). It is concluded 1) that residual IGF-binding proteins in acid-ethanol extracts may cause considerable error in IGF-II measurements, and 2) that this interference can be completely blocked by excess IGF-I, if highly specific antisera are used.
Adolescent↗
Clinical relevance of serum measurements of insulin-like growth factors and somatomedin binding proteins.
With the presently available RIAs, serum levels of IGF-I, IGF-II and somatomedin binding protein can be determined specifically. Basal IGF-I and binding protein levels are low in GH deficiency, and normality of these parameters virtually excludes the condition. If, in a given clinical situation, auxological criteria and IGF-I (binding protein) levels suggest GH deficiency but the diagnosis is rejected by conventional stimulation tests, a further diagnostic work-up is needed, including measurements of spontaneously secreted GH. IGF measurements may serve as tools to disclose the unknown pathogenesis in growth disorders. Short-term responses of IGFs to exogenous GH may assist in defining the GH doses required to induce long-term growth.
Adolescent↗
[Somatomedins].
Somatomedins are peptide hormones with insulin-like structure and effects. Their synthesis is governed by growth hormone. Somatomedins stimulate growth of cartilage tissue and other tissues. Synthesis of somatomedins occurs in various tissues, predominantly in the liver. For clinical practice determinations of somatomedin C (= IGF I) levels in blood have become valuable, since they give insights into the growth hormone secretory state, being low in growth hormone deficiency and high in acromegaly. In other growth disorders somatomedin C measurements can give new insights into the underlying pathogenesis. The role of IGF II and other peptides with somatomedin-like characteristics is presently under investigation.
Acromegaly↗
Clinical experience with authentic recombinant somatropin--German Collaborative Study.
A multicentre clinical trial with recombinant somatropin was initiated in West Germany in early 1986. Acceptance of patients to the study was determined according to criteria outlined in a detailed study protocol. To the present time, 41 patients with hGH deficiency not previously treated (naïve) and 28 patients previously treated with pituitary hGH have been admitted. Recombinant somatropin is given, 12 IU/m2/week s.c., divided into six doses. Height velocities during treatment rose dramatically for naïve patients from 3.5 cm/year (n = 40, before treatment), to 15.0 cm/year (n = 19, calculated at 3 months), and 13.3 cm/year (n = 8, calculated at 6 months). For previously treated patients, the increase in height velocity was from 5.8 cm/year (n = 20) to 9.2 cm/year (n = 19, after 3 months) and 8.6 cm/year (n = 9) at 6 months. Tolerance of recombinant somatropin was good, and no anti-hGH antibodies were detected in any of the patients.
Antibody Formation↗
A note on adults with growth hormone deficiency.
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Adult↗
Plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone response to corticotropin-releasing factor in normal children during pubertal development.
The adrenocorticotropin (ACTH), cortisol, and dehydroepiandrosterone responses to synthetic human corticotropin-releasing factor (CRF) were studied in 28 endocrinologically healthy children (age 1-16 yr) and in six adult volunteers (age 24-42 yr). CRF was given as an intravenous bolus (1 microgram/kg body weight) between 0900 and 1000 hr. Significant increments in ACTH and cortisol levels after CRF were observed in all subjects, with an ACTH peak value of 48.2 +/- 3.4 pg/ml at 10 min (p less than 0.001). The ACTH and cortisol response patterns after CRF did not change with age or pubertal maturation and did not differ in children and in adults. In contrast, the dehydroepiandrosterone response to CRF clearly was related to the stage of pubertal development. The peak value after CRF significantly increased from puberty stage 1 to puberty stage 5 (164 +/- 18 versus 779 +/- 86 ng/100 ml, p less than 0.001). In adults, the mean dehydroepiandrosterone peak value after CRF did not differ from that of P5 children. These results show that CRF can be given safely to children. The absence of age-dependent ACTH and cortisol responses and a dehydroepiandrosterone response changing with pubertal maturation points to the existence of factors involved in the control of adrenal androgen production other than ACTH.
Adolescent↗
The effects of cyproterone acetate on statural growth in children with precocious puberty.
Forty-four patients (42 f, 2 m) with precocious puberty (31 idiopathic, 1 familial, 7 cerebral, 5 McCune-Albright) were treated with cyproterone acetate for periods of 1-8.75 years in different (P less than 0.05) daily dosages of 117 +/- 6.1 mg/m2 per day (mean +/- SEM, group A, N = 20) and 60.8 +/- 2.42 mg/m2 per day (group B, N = 24). Thirty-three girls had experienced menarche before therapy at a mean age of 4.89 +/- 0.42 years. Treatment was started at a chronologic age of 5.45 +/- 0.33 years in the girls and 5.74 +/- 1.34 years in the boys. At the time of evaluation, 31 of our patients had reached final height. With respect to the effects of treatment on statural growth, the Standard Deviation Scores were retrospectively determined for height, weight, and growth velocity. The initial Bayley-Pinneau height predictions were compared with final height and target height, and the skeletal maturation was studied. There were no significant differences between those parameters in the patients of group A and B or between treated and untreated subjects as far as final height and target height were concerned. It is concluded that cyproterone acetate administered orally at daily doses from 50-150 mg/m2 does not improve statural growth of patients with precocious puberty.
Body Height↗
Growth hormone, somatomedin levels and growth regulation in Turner's syndrome.
In a total of 56 children and adolescents with Turner's syndrome (41 with karyotype 45,X) basal serum levels of somatomedin bioactivity, Sm-C/IGF-I (RIA), IGF II (RIA), GH response to arginine and GHRH (GRF(1-29)NH2), and spontaneous GH secretion during 5.5 h of deep sleep were determined in a cross-sectional manner. GH responses to GRF and arginine as well as IGF-II levels were found to be in the normal range. Levels of somatomedin bioactivity were higher than normal before a bone age of 10 years, in the low-normal range thereafter, and below normal in some patients. Levels of Sm-C/IGF-I were found normal before and low-normal after a bone age of ten years. There was a trend towards increasing Sm-C/IGF-I levels with age. In contrast to the normal pattern, spontaneous sleep-related GH secretion was declining with age and did not show the puberty-associated rise. These findings suggest a normally functioning growth hormone-somatomedin axis in Turner's syndrome with alterations of its functioning level occurring secondarily as a result of absent gonadal activation. In single patients abnormally low growth hormone and/or somatomedin secretion may be present.
Adolescent↗
The polymorphic pattern of somatomedins during human development.
Human somatomedins (Sm) are heterogeneous on separation by chromatofocussing. Besides the 'classic' insulin-like growth factor I and II (IGF-I/Sm-C and IGF-II), a number of minor peaks emerge which can be classified as IGF-I/Sm-C-like or as IGF-II-like. The aim of the current study was to investigate whether or not polymorphism of somatomedins is present in individuals and whether or not the polymorphic pattern changes during development. Serum extracts from normal healthy children and adults were fractionated by chromatofocussing and the various somatomedin-like peptides were quantitated by specific radioimmunoassays for IGF-I/Sm-C or IGF-II. The results demonstrate 1) that heterogeneity of somatomedins is a common phenomenon existing in all individuals studied, and 2) that the polymorphic patterns of the IGF-I/Sm-C-family and of the IGF-II-family remain rather stable during development, although minor changes are evident.
Adolescent↗
Human growth hormone therapy of non-growth hormone deficient children.
With biosynthetically derived human growth hormone (hGH) available in large quantities, attempts will be made to promote growth in short children who do not fulfill the 'classical' criteria for growth hormone deficiency (GHD). By these criteria, GHD is excluded if hGH levels to pharmacological stimuli exceed a definite level. Several studies have shown that a variety of short children, who are not growth hormone deficient by these criteria, will demonstrate an increased growth rate with hGH treatment. A subpopulation of children with clinical features of GHD, delayed bone age and low somatomedin levels, have low levels of spontaneously secreted growth hormone or 'bioinactive' growth hormone. These children increase their growth rates to substitution doses of hGH. In other children whose growth disorder is not likely to be caused by a disorder in the growth hormone-somatomedin axis, growth increments are occasionally seen on higher hGH doses. Future long-term studies--carefully considering the ethics of such approaches--will have to evaluate the relationships between hGH dose and both metabolic and growth responses and side effects in children with short stature in order to define more specifically further target groups of short children who will benefit from hGH therapy.
Body Height↗
[Therapy of pituitary dwarfism with recombinant human growth hormone. A multicenter study].
During the period from 1982 to 1985, biosynthetic growth hormone (methionyl-hGH) was administered to 55 children with pituitary growth deficiency, 49 with idiopathic, six with other forms of the disorder. Preparations with a relatively high content of Escherichia coli polypeptides (ECP) were given to 32 children (group I), those with a markedly reduced ECP content to 12 (group II), while 11 children received almost ECP-free preparations (group III). The treatment achieved an intensive rise of growth acceleration in all three groups. At the same time, somatomedin C, biological somatomedin activity and alkaline phosphatase rose steeply, reaching a maximum after six months and remaining at high concentrations even thereafter. High antibody titres against ECP and hGH (with high binding capacity) were demonstrated in group I children, significantly lower titres with little binding capacity in those of group II, while most of those in group III had no measurable antibodies. Even in high concentrations the antibodies did not have any inhibiting effect on growth. No positive correlation between antibody titre and growth velocity was demonstrable. An exception was a boy with an allergy in group I, who had a maximal antibody titre and, at the same time, a high serum concentration of IgE. He had marked delay in growth which, however, quickly became normal on administration of extractive hGH.
Bacterial Proteins↗
Testing with growth hormone-releasing factor (GRF(1-29)NH2) and somatomedin C measurements for the evaluation of growth hormone deficiency.
Growth hormone (GH) responses to GRF (1 microgram/kg BW i.v.) were investigated. Comparison between GRF(1-40) and GRF(1-29)NH2 in 11 young adult volunteers gave identical results. One hundred and thirty-one children and adolescents (45 with idiopathic GHD) were tested with GRF (1-29)NH2. The maximal GH levels (max GH) in response to GRF during the 120 min test period were found suitable to characterize the response. In cases without GHD no correlation to age, sex and pubertal development was observed. A maximal GH level of above 10 ng/ml was found to be normal. In 3 out of 86 children without GHD (one with Turner syndrome; two with simple obesity) max GH fell short of 10 ng/ml, while 11 of 45 cases with GHD exceeded this margin. In GHD, max GH was inversely correlated with age. There was no difference in max GH between groups with or without perinatal pathology as a presumed cause of GHD. GH levels to GRF were positively correlated with maximal GH level during sleep in GHD, but not correlated with responses seen to insulin or arginine. The value of GRF testing for the confirmation of GHD is discussed in the light of other GH stimulatory tests and basal somatomedin C measurements. It is suggested that the combination of testing with GRF and the determination of a basal SmC level offers a safe and convenient way to diagnose GHD in clinically suspected cases, though in some cases further diagnostic tests may be needed.
Adolescent↗