Constitutional delay of growth and adolescence. Results of short-term and long-term treatment with GH.

During recent years numerous reports on the favourable results of short-term trials with GH in patients with constitutional delay of growth and adolescence (CDGA) have been published, but it has been unclear whether such treatment affects final height. In the present study, the results of long-term therapy with GH in replacement doses have been evaluated in 15 patients who were treated with GH for several years (three years on average). At the start of treatment, 10 of the children were prepubertal and 5 were in puberty. All patients were followed up until final height was reached. Mean final height of the 13 male patients was 170.0 +/- 4.4 cm, i.e. -1.58 SDS. In the two female patients, final height was 150.0 cm (-3.5 SDS) and 164.0 cm (-0.8 SDS), respectively. Adult height of the patients lagged behind target height by 5.4 +/- 3.2 cm (mean +/- SD). Measured adult height corresponded to adult height as predicted prior to treatment. In conclusion, GH treatment of patients with CDGA did not increase final height.

Aetiology and pathogenesis of growth hormone deficiency.

Growth hormone deficiency (GHD) represents an aetiologically non-uniform disorder: it can have multiple causes. Three main groups can be differentiated: (1) GHD due to manifest organic alterations of the hypothalamo-hypophyseal system; (2) so-called idiopathic cases; and (3) genetically determined forms. The first group comprises the congenital malformations, affecting the midline structures of the brain more often than the pituitary itself, and the acquired lesions, mainly tumours, which are generally suprasellar rather than intrasellar. The large majority of the so-called idiopathic cases result from perinatal damage which affects the hypothalamus more often than the pituitary proper. Births in non-cephalic positions, in particular breech deliveries, play a significant role, but other difficult parturitions of prolonged duration also lead to such damage. With improved obstetric techniques, particularly the more frequent use of caesarean section, such lesions now occur far less frequently than 30 years ago. In the last 20 years, several genetically determined disorders associated with GHD have been described, four of them with isolated GHD, three with multiple deficiencies of pituitary hormones. Most cases are inherited by autosomal recessive transmission.

Constitutional delay of growth and adolescence.

Constitutional delay of growth and adolescence (CDGA) is characterized by simultaneous retardation of growth, skeletal maturation and sexual development. Primarily longitudinal growth is impaired. The late occurrence of puberty is a secondary phenomenon brought about by the retarded physical development. Plasma levels of sex hormones and gonadotrophin correlate with bone age, not with chronological age. The provocation tests for growth hormone (GH) show normal results. In contrast, the spontaneous secretion of GH, measured half-hourly through the night or over 24 hours, is markedly reduced. Plasma somatomedin C is diminished. According to these data, CDGA is not a genuine GH deficiency but represents a cybernetic disorder coinciding with a false threshold for GH. As shown by large series of investigations, the final height of the patients lies on average 1.85 SD below the mean of healthy adults, with large individual variations. The decision as to whether treatment by growth promoting hormones should be performed should be made with regard to the individual height prognosis. With GH in physiological doses growth velocity can be considerably increased. Bigger doses of the hormone appear to be necessary in order to enhance final height. Treatment by anabolics and testosterone increases height velocity only, not adult height.

New observations on midline defects: coincidence of anophthalmos, microphthalmos and cryptophthalmos with hypothalamic disorders.

Four children with severe congenital eye anomalies are described of which three had related symptoms. Two had bilateral anophthalmia, the optic nerves not detectable by computed cranial tomography and magnetic resonance imaging, and the third child had bilateral microphthalmia and coloboma iridis. The fourth patient had bilateral cryptophthalmia as part of Fraser syndrome. All four patients were of small stature. In three of them growth hormone deficiency was demonstrated which was of hypothalamic origin as shown by growth hormone releasing hormone tests. In the fourth child hypogonadotropic hypogonadism and tertiary thyroid deficiency were diagnosed which responded well to thyroxine treatment. Pathogenetically the described disorders are due to congenital defects of midline structures as a common "developmental field".

A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency.

The acid-stable subunit of the GH-dependent large mol wt somatomedin-binding protein (SmBP) was isolated from human plasma Cohn fraction IV by a three-step procedure, and a specific RIA was developed which allowed measurement in unextracted serum. Although in normal human serum most of immunoreactive material was present as the large mol wt complex (150K), considerable amounts of smaller components were found by high performance liquid exclusion chromatography in the 60K, 42K, and 32K range. Normal serum levels were low at birth, rose sharply during the first weeks of life, and showed a moderate peak at puberty. To assess the diagnostic efficacy of SmBP for GH deficiency (GHD), patients previously diagnosed as GH-deficient by conventional criteria (n = 132) were compared to short statured children without GHD (n = 130). Taking the fifth centile as a limit of normality the majority of patients with GHD had subnormal levels, yielding high sensitivity of the test (0.97). In contrast, most of the non-GH-deficient children had SmBP levels within the normal range, resulting in high specificity (0.95) and, consequently, high accuracy (0.96). These results suggest that the large mol wt SmBP is an excellent screening parameter and is highly informative for GHD.

[Natural science and humanitarian aspects of medicine]. / Naturwissenschaftliche und humanitäre Aspekte der Medizin.

In the 19th century the natural sciences took a rapid rise, connected with a mainly biological interpretation of all vital processes. To the physician fell the role of the analytical observer who--according to the findings obtained - made a precise diagnosis which in consequence led to the adequate therapy. Patient and disease were the objects of observation and treatment. In the twentieth of our century a radical change took place. R. von Weizsäcker and R. Siebeck established the "anthropologic medicine" resp. the "medicine of the person" where the doctor and the patient enter into a personal relationship. The significance of the patient's biography in the course of this disease was recognized. The "psychosomatic medicine" was developed. Our own time requires the reorientation to those values and principles and, moreover, and improved integration of the advanced medical technology.

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.

[Spontaneous secretion of growth hormone in deep nocturnal sleep. II. Studies on hypophyseal dwarfism and constitutional developmental delay]. / Spontansekretion des Wachstumshormons im nächtlichen Tiefschlaf. II. Untersuchungen bei hypophysärem Minderwuchs und bei konstitutioneller Entwicklungsverzögerung.

To evaluate the somatotropic function of the pituitary, the measurement of the spontaneous nocturnal secretion of GH is a rather suitable method. Whereas the provocation tests check the capacity of the gland after intensive stimulation, spontaneous secretion reflects the behaviour of the hypothalamohypophyseal system under everyday conditions. The investigation of 65 children with pituitary dwarfism showed in all cases a strong diminution of the GH secretion. Overlapping with the control group was hardly seen. The maxima measured during sleep were identical with those reached in the provocation tests. The subdivision in complete and partial GH deficiencies is more precise with measuring the spontaneous secretion than with provocation tests. Nocturnal spontaneous GH secretion was determined in 128 patients with constitutional delay of growth and adolescence. Also in these children provocation tests were performed simultaneously. Spontaneous GH secretion was found significantly diminished in all stages of puberty, compared to the controls (p less than or equal to 0.01). By contrast, the provocation tests showed no significant differences from controls. According to these results, the retarded growth of the patients is due to a relative GH deficiency. As is evident from the normal results of the provocation tests, no organic insufficiency of the pituitary is demonstrable. Rather a cybernetic disorder is responsible for the reduced hormone secretion.

Therapy with growth hormone--old and new indications.

Pituitary dwarfism with severe growth hormone deficiency (GHD) represents the classical indication for treatment by recombinant human growth hormone (hGH). With continuous GH replacement and early start of treatment, normal adult height can be achieved. During puberty the dosage of hGH administered should be increased. Numerous growth disorders do not coincide with major GHD as determined by provocative tests but only with diminished spontaneous hormone secretion. Typical examples are constitutional delay of growth and adolescence and growth retardation after irradiation of the skull. Also in these disorders treatment by recombinant hGH in replacement doses renders favorable results. The more normal the spontaneous GH secretion is, e.g. in familial short stature and in skeletal dysplasias, the higher doses of GH are needed to stimulate growth. For treatment of patients with Turner's syndrome a combined therapy with high doses of GH and with oxandrolone has proven rather effective. With endogenous and exogenous hypercortisolism the metabolic balance is shifted towards catabolism and spontaneous GH secretion is depressed. In such situations, e.g. after severe traumas, operations, infections and combustions, administration of GH can be rather helpful. Recent trials in children with stunted growth due to chronic renal insufficiency show that it is possible also in this condition to effectively stimulate growth by hGH.

Growth hormone therapy in short children without classical growth hormone deficiency.

The spontaneous secretion of GH which determines the growth in height as well as the GH increment in the provocation tests (the socalled pituitary reserve) is diminished in pituitary dwarfism. In numerous other growth disorders only the spontaneous GH secretion is impaired. Amongst others this is true of the syndrome of constitutional delay of growth and adolescence which is the most frequent growth disorder in childhood and of the growth retardation after X-ray irradiation of the skull. In all these cases treatment by hGH represents replacement therapy. In children with intrauterine growth retardation, familial short stature and skeletal dysplasias growth hormone deficiency cannot be proved. In most cases the growth velocity cannot be accelerated with hGH in the usual replacement doses. High doses of hGH may be successful. In endogenous and exogenous hypercortisolism the spontaneous GH secretion is suppressed and the effect of the somatomedins on the growing cartilage is inhibited. This is not only true of Cushing's Syndrome and corticosteroid therapy but also of cases of glycogenosis Type I. The resulting growth retardation can - at least partly - be overcome with hGH. Preliminary investigations show that the growth retardation in children with chronic renal failure can successfully be treated by hGH.

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.

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.

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.

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.

Clinical experience with recombinant somatropin: German collaborative study.

A multicentre 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. A total of 62 patients with GH deficiency has now been treated with recombinant somatropin for a minimum of 12 months. Of these, 34 were previously untreated and 28 had previously received pituitary GH. Recombinant somatropin, 12 IU/m2/week, was administered subcutaneously, divided into six doses. Height velocities increased from 3.4 cm/year (pretreatment) to 10.4 cm/year in the previously untreated group, and from 6.0 cm/year during the last year on pituitary GH to 8.3 cm/year for the previously treated patients. Tolerance of recombinant somatropin was good, and no anti-GH antibodies were detected in any of the patients.

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.

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.