Primordial Dwarfism Research Articles

102: Study of serum GH by radioreceptor assay in normal and constitutionally short children

A growth hormone radioreceptor assay (RRA) was developed using the 100,000 g pellet from pregnant cortisone-treated rabbit liver homogenate, the 125 I hGH binding being specifically and completely displaced by unlabelled hGH. Sensitivity was 0.2 ng. Comparing the GH levels found by this method and by radioimmunoassay in normal sera, the mean RRA/RIA ratio was 0.84 ± SEM 0.07 (range 0.70/0.93). In 11 out of 16 primordial dwarfs the RRA/RIA ratio was in the normal range; it was lower in 2 and higher in 3. But in a number of samples from primordial dwarfs the curve of displacement of labelled GH from the receptor did not parallel the standard curve. This phenomenon was not due to anti-hGH antibodies, it was not induced by addition of insulin and was not modified when variable amounts of hGH were added to these sera. It may be concluded 1/ that serum levels of GH estimated by RRA are generally lower than by RIA; 2/ that individual discrepancies are found in primordial dwarfs; 3/ that the serum from certain primordial dwarfs modifies the affinity of GH for the receptors.

Nocturnal growth hormone secretion: correlation with sleeping EEG in adults and pattern in children and adolescents with non-pituitary dwarfism, overgrowth and with obesity.

ABSTRACT Half-hourly blood samples and continuous EEG recordings were obtained during nocturnal sleep in ten adults in whom a special sampling system working from the adjacent room was used in order not to disturb the sleep. In nine of the ten adults the first D/E-stage during sleep was accompanied by a significant increase in plasma growth hormone (HGH) (2.5 to 31.8 ng/ml). Of 16 subsequent D/E-stages only three were accompanied by HGH peaks. Similar studies but without EEG recordings were done in 25 children and adolescents. HGH peaks comparable to those seen in adults occurred in normal children, children with constitutional or primordial dwarfism, with retarded growth associated with renal or with miscellaneous diseases and in children with overgrowth. These peaks frequently seemed to coincide with periods of deeper sleep as judged from observation of the children. There was no evidence that HGH peaks occurred less often or were smaller in dwarfed children or that children with overgrowth had higher or more frequent HGH peaks. However, fewer and smaller HGH peaks were seen in obese children, whether or not obesity was associated with overgrowth. There was no correlation between nocturnal HGH peaks and variations in the concentration of blood sugar (BS), free fatty acids (FFA) or immunoreactive insulin (IRI). No apparent correlation could be seen between the height of the nocturnal HGH peaks and the response of plasma HGH concentration to provocative stimuli. It is concluded that nocturnal HGH peaks are related to, but not exclusively determined by phases of slow-wave sleep. They are not due to disturbance of sleep by the sampling procedure. Their pattern is the same in adults, normal children and in children with non-pituitary dwarfism or overgrowth. Obese subjects often have fewer and smaller nocturnal HGH peaks even when obesity is associated with overgrowth.

Factors affecting growth in man.

Growth is a complex process dependent upon the interaction of many factors. Deficiencies in some of these result in obvious clinical syndromes such as juvenile myxoedema or hypopituitarism. In many other clinical states, for instance primordial dwarfism, we are still far removed from the full explanation and the solution is likely to come from detailed biochemical study of the mechanisms of action of growth hormone and related factors in health and disease.

Metabolic clearance and production rates of human growth hormone in subjects with normal and abnormal growth.

ABSTRACT The metabolic clearance rate (MCR) and production rate (PR) of human growth hormone (HGH) was estimated bymeans of a continuous infusion of 131I-HGH. Forty-four subjects, ages 4½–60 yr, with normal and abnormal growth, participated in this investigation. A significant correlation (p <.01) was found between MCR and surface area. The MCR/m2 was similar in childhood, adolescence and adult life. The MCR/m2 in ml/min (mean ±se) in 9 normal males (112 ±5) was similar to that in 8 normal females (111 ±10). The results found in hypopituitary (109 ±8) and acromegalic (118 ±16) individuals indicate that the MCR/m2 is independent of plasma HGH concentration. The MCR of HGH was normal in patients with delayed adolescence, hyperthyroidism and gonadal dysgenesis. Reduced MCR was seen in severe hypothyroidism and in one form of primordial dwarfism. The production rate (PR) of HGH in normal patients, calculated on the basis of mean plasma hormone levels, is significantly higher than that observed in hypopituitar...

Metabolic rates during recovery from protein-calorie malnutrition: the need for a new concept of specific dynamic action.

OPINION is still divided as to whether the metabolic rate of malnourished infants is increased or decreased, or whether, indeed, it remains the same1–17. The conflicting evidence probably arises from lack of suitable standards of reference and differing interpretations of the basal state. In addition, the term malnutrition or under-nutrition has been applied to a variety of clinical conditions from primordial dwarfism to simple fasting. The confusion, however, is small in comparison with that surrounding the phenomenon of specific dynamic action. The present study has the disadvantage of having to deal with both of these difficult issues.

Studies on adrenal cortex reserve function of the adrenal cortex in children with total urinary 17-hydrooxycorticosteroids as an indicator. 2. Its urinary excretion by successive loading of ACTH in various pediatric diseases

Following the previous report, the author intended, in this study, to investigate how the adrenal cortex of children with various diseases respond to the administration of adrenocorticotropin (ACTH). The subjects consisted of 32 cases with endocrine or metabolic diseases, 11 cases with central nervous disease and 22 cases who were previously treated with corticosteroids. Daily doses of 20 units ACTH-Z were given intramuscularly for 2 to 5 days, and the urinary total 17-hydroxycorticosteroids (17-OHCS) excretion was determined. The results were compared with those obtained from the healthy infants and children which were described in the previous report.1) Diseases of endocrine and metabolism i) Dwarfism-The response in two of six examined cases with pituitary dwarfism showed the prolonged type (prolonged response). In a patient with progeria no significant elevation of urinary 17-OHCS excretion was observed during the administration of ACTH. However, such abnormal responses were observed in none of six cases with primordial dwarfism. ii) Obesity-The response in three of eight cases with simple obesity showed the excessive type (excessive response). On the contrary, two of six cases with Laurence-Moon-Biedl syndrome showed the prolonged response.iii) Miscellaneous Diseases-No abnormal response was obtained in the cases of chondrodystrophia foetalis (two cases), gargoylism (two cases) and leucine sensitive hypoglycemia (one case).2) Diseases of central nervous system i) Cerebral palsy-Two of six cases examined showed the weak response, which the author described as the “transitory” type. Other types of abnormal response, such as the prolonged response, excessive response were also obtained in this disease.ii) Brain tumor-One of five cases examined showed the prolonged response and the other one showed the excessive response.3) Children with a previous administration of corticosteroids. Nine of twenty-two cases examined showed the prolonged response. No significant relation between the appearance of this response and the ages of the subjects was found.4) The adrenocortical responsiveness of children, subjected for the study, was commented according to the above-mentioned results.

Studies with human growth hormone (HGH): An attempt to correlate metabolic response during short-term administration with linear growth during prolonged therapy

All fifteen patients (twelve hypopituitary dwarfs, one primordial dwarf and two patients with gonadal dysgenesis) studied exhibited one or another metabolic response to human growth hormone (HGH) during initial short-term studies. Decreased urinary nitrogen, increased urinary calcium and increased urinary hydroxyproline: creatinine ratio were observed in all patients so studied. All twelve hypopituitary dwarfs showed a significant fall in serum urea nitrogen. The magnitude of the various responses to HGH varied in individual patients. No effect of the short-term administration of HGH could be used to predict the response in linear growth to prolonged therapy with the possible exception of minimal nitrogen retention (< 1.0 gm. per day). The data presented here suggest that the administration of HGH, 5 mg. daily for six days, will correct reactive hypoglycemia but that a longer period of treatment is necessary for correction of sensitivity to exogenous insulin. No increase in growth rate was observed in the primordial dwarf treated for six months with Wilhelmi HGH, (W HGH), 2 mg. daily for the first fourteen days of each twenty-eight day cycle. Two patients with gonadal dysgenesis treated in a similar manner with 5 mg. of HGH daily showed accelerated linear growth. All preparations of HGH used were metabolically active, including two preparations from pituitaries from embalmed bodies. All three of the preparations of HGH, including one from pituitaries from embalmed bodies, used for prolonged treatment were capable of stimulating growth rate. A comparison of the potency of the various preparations is not possible due to the limited use of any HGH other than that extracted by Wilhelmi. During initial metabolic studies the administration of HGH was equally effective when the total dosage was given in one dose daily or in divided doses. No unequivocal evidence for contamination of the HGH with TSH, ACTH or gonadotropins was obtained. Ten of twelve hypopituitary dwarfs showed accelerated growth when given 2 mg. of HGH daily for the first fourteen of each twenty-eight days. One patient failed to respond at this dosage level but showed comparable response to a dose of 5 mg. HGH. Patients receiving more than one eight-month course of injections of HGH, using the same dosage and preparation, exhibited diminished growth response during succeeding courses. This waning effectiveness occurred in one patient despite increases in the dose.

Growth Disorders in Child and Adolescents.

Although current limited availability of human growth hormone has been responsible for renewed interest in the small child, the old questions are as troubling as before: what size is to be considered sufficiently small to be rated as abnormal? How much investigation and what type of investigation is most reasonable in evaluation of the problem of growth retardation? To a large extent, Dr. Kaplan's book is addressed to these questions and provides answers that are about as helpful as can be offered at present. Patterns of normal growth are considered in some detail. Primordial dwarfism, growth retardation resulting from diseases of specific systems, and various endocrine disorders associated with abnormalities of growth are reviewed. Recently acquired knowledge concerning growth hormone is considered in detail and interpreted in clinical perspective (the author concludes that deficiency of growth hormone is a rare cause of growth retardation). Discussion of indications and contraindications for

Effect of Urinary Growth Hormone Described

Marked differences may be apparent in the urinary growth hormone levels of patients with short stature of different etiologies, two investigators from the Albert Einstein College of Medicine, Bronx, NY, have discovered. Jack Geller, MD, and Arthur Loh, MA, reporting at the 46th meeting of the Endocrine Society in San Francisco in June, suggested that the differences in urinary growth hormone levels may reflect the etiology of dedevelopmental retardation. Using immuno-assay techniques the investigators measured growth hormone levels in extracts of urine from persons of normal size and from patients with short stature due to: ( 1 ) constitutionally retarded development characterized by proportional retardation in height age and bone age; (2) primordial dwarfism; and (3) primary bone disorders. Normal values of growth hormone in 24-hour urine extracts were found to range from 10 to 125μgm. In 13 of 15 short stature patients with constitutionally retarded development, urinary growth hormone levels were

Human growth hormone in dwarfism since birth.

In the few years which have passed since the introduction of human growth hormone (HGH) in clinical research, it has been well documented that the hormone promotes growth in pituitary dwarfs.^1-8This effect has so far not been found in primordial dwarfs^1,2or in normal children⁹when treated with HGH in doses that will produce growth in pituitary dwarfs. Growth response to HGH has been reported in several children in whom no endocrine abnormality could be demonstrated. It has, however, been suggested that these children may have been deficient in growth hormone.^5,8 It is the purpose of this paper to report the results of HGH treatment in a 2½-year-old boy with retarded bone age, who manifested dwarfish growth from birth. Although physical and laboratory findings did not suggest panhypopituitarism, his response to HGH treatment was both qualitatively and quantitatively similar to that encountered in pituitary dwarfs.

GROWTH DISTURBANCES AND VALUES FOR HORMONE EXCRETION IN VARIOUS FORMS OF PRECOCIOUS SEXUAL DEVELOPMENT

Forty-two children with precocious sexual development have been classified according to: a) constitutional sexual precocity, b) premature adrenarche, and c) premature thelarche. Constitutional sexual precocity and premature adrenarche are associated with excessive growth, advance in bone maturation, and elevation of the urinary 17-ketosteroids. In contrast, in premature thelarche growth, bone maturation and 17-ketosteroids were normal. The presence of estrogenization of the vaginal smear was the most helpful laboratory finding in differentiating constitutional sexual precocity from the other two conditions. The presence of detectable urinary gonadotropins in precocious puberty is of limited help. Two patients with primordial dwarfism and associated precocious puberty are reported. The occurrence of constitutional precocious puberty in a brother and a sister is described. This is apparently the first reported instance in which familial precocious puberty occurs in either sex.

Metabolic studies with human growth hormone in dwarfism and acromegaly.

Human growth hormone failed to cause nitrogen retention in 4 primordial dwarfs. In 3 of 4 other children, there was a small but distinctly positive nitrogen balance. The primordial dwarfs were not completely refractory to human growth hormone since it caused an increase in the level of plasma unesterified fatty acid and an increase in urinary calcium excretion. In 4 adult patients with acromegaly, human growth hormone was ineffective as an anabolic agent. It did, however, cause an increase in the urinary excretion of calcium. Since 2 of the 4 subjects had clinically inactive disease, it is proposed that the tissues of these subjects had responded maximally to endogenous HGH and subsequently maintained this response. The administration of androgen resulted in nitrogen retention, indicating different sites or mechanisms of deposition of protein.

Human growth hormone: II. Further study of its effect on growth in dwarfism

Summary A “hypopituitary” dwarf was treated during a 10-month period with human growth hormone (Raben12); there was a resultant spurt in growth associated with relatively slight, if any, maturation in body proportions and skeleton. Radiologic evidence of widening of the epiphyseal plates was noted. A constitutional or primordial dwarf was treated with similar amounts of growth hormone and failed to show significant reduction in urine nitrogen, changes in blood chemistries, or a spurt in linear growth. Neither patient had any apparent adverse reaction to the growth hormone.