The Brush Foundation studies on human growth and development, begun in 1931 and terminated in 1942, have been intensively reviewed and studied by Dr Greulich and Miss Pyle in the formulation of this Radiographic Atlas of Skeletal Development of the Hand and Wrist Serial radiographs of from 2 to 20 hand-films made at successive examinations of each of 1000 boys and girls made up the radiographic material Standards were selected that were judged to be the most representative of the central tendency or anatomic mode of each chronologic age group from birth through 18 years

Radiographic Atlas of Skeletal Development of the Hand and Wrist

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

THE CLASSICAL CONCEPT of neuroendocrine control of the pituitary as proposed by Harris stipulates that the endocrine functions of the anterior pituitary are controlled by hypothalamic releasing factors or release-inhibiting factors. It was postulated that these factors are present in hypothalamic neurons which project into the median eminence (ME) of the basal hypothalamus and end in contact with the hypothalamic-hypophyseal portal vessels (1). It has subsequently been shown that growth hormone (GH) secretion is regulated by both stimulatory and inhibitory factors of hypothalamic origin. Like other anterior pituitary hormones, GH is secreted episodically. In all mammalian species so far studied spontaneous episodes of GH secretion occur several times over a 24-h period (2–8). Particularly in the adult male rat there is a striking regularity in the GH pulses which occur at 3- to 4-h intervals and reach levels of several hundred ng/ml.

Sexual dimorphism in the control of growth hormone secretion.

Objective: Low birth weight remains a major cause of morbidity and mortality in early infancy and childhood. It is associated with an increased risk of health problems later in life, particularly coronary heart disease and stroke. A meeting was convened to identify the key health issues facing a child born small for gestational age (SGA) and to propose management strategies.

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Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society

We examined changes in spontaneously secreted growth hormone with aging by studying the 24-h integrated concentration of GH (IC-GH) of 173 nonobese subjects (height, greater than or equal to 5%; 7-65 yr of age). There was no significant difference in IC-GH on repeat testing of 13 men or in 23 women studied in the follicular and again in the luteal phase of the menstrual cycle. The level of IC-GH was strongly effected by age; children had the highest mean IC-GH, and there was a decline in IC-GH with increasing age after the second decade of life. The correlation of IC-GH with age was highly significant (r = 0.73; P less than 0.0001). There was no difference in IC-GH between males and females when matched for age. The mean IC-GH at Tanner stage 5 of puberty (7.4 +/- 2.0 ng/ml) was higher than that at stages 2-4 (5.7 +/- 1.4; P less than 0.0005) or that in prepubertal children (5.8 +/- 1.4; P less than 0.001). Thus, age and pubertal status must be carefully considered when interpreting the IC-GH for patients suspected of having deficient or excessive secretion of GH.

The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals.

A micropenis is an abnormally small penis with a normal configuration. This finding constitues a sign not a diagnosis. The etiologies may be classified as hypogonadotropic hypogonadism, primary hypogonadism, androgen insensitivity, or idiopathic; among 45 patients, the respective percentages in these categories were 31, 24, 2 and 7% with 36% as yet undiagnosed. Various clinical syndromes may include a micropenis and can be classified in one of the etiologic categories. This paper provides the criteria for determining the presence of a micropenis. A phallic length which is 2.5 or more standard deviations below the mean should be considered as abnormal; for an infant of 0 to 5 months of age, the lower limit is 1.9 cm. The technique of penile measurement, determination of etiology, guidelines for sex of rearing and psychologic, surgical and medical management are discussed.

Micropenis. I. Criteria, etiologies and classification.

of dental development comes from congenital cretins and individuals with acquired juvenile hypothyroidism. The role of the growth hormone (GSH) is separately evident in hypopituitarism and, less clearly, in the panhypopituitary state. Children with the adrenogenital syndrome and precocious puberty, if of prolonged duration, tend to be advanced in dental development, though hormonal specificity is less clear in such conditions. In theory, the XO might be expected to resemble the normal XV in the timing of dental development, but in practice the XO with multiple defects of dental development, juvenile osteoporosis, and immunological peculiarities can no longer be considered as a simple example of ovarian agenesis. -S. M. G.

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Endocrine factors in dental development.

Extract: Six patients with the syndrome of congenital adrenocortical unresponsiveness to ACTH are reported This syndrome is characterized by feeding problems early in life, hypoglycemic episodes and hyper-pigmentation of the skin (table I) Blood pressure and levels of electrolytes in serum were normal (table II) PPD and histoplasmin skin tests were negative, while antibodies to adrenal, thyroid, and gastric tissues were undetectable Urinary excretion of 17-hydroxycorticosteroids and cortisol production rates were low and did not respond to administration of ACTH (table III) While receiving a low sodium diet, the patients were able to conserve sodium (figs 2, 3 and 4) and to increase the rate of aldosterone secretion (tables IV and V) In one case, adrenal pathology showed a normal zona glomerulosa with atrophy of the zonae fasciculata and reticularis This isolated deficiency in cortisol secretion is not due to a defect in pituitary function or a deficiency of one of the enzymes directly involved in steroid biosynthesis The most probable pathogenesis is an abnormality at the site (or one of the sites) of ACTH action on cortisol biosynthesis Speculation: It is probable that some young infants in whom a diagnosis of Addison's disease is made do, in fact, have the syndrome of congenital adrenocortical unresponsiveness to ACTH Studies of cortisol secretion rates prior to and during ACTH administration and a determination of aldosterone secretion rates while receiving normal and low salt diets will permit differentiation of the two disorders

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The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases.

Precocious puberty in a boy with hepatoma and circulating gonadotropin.

Extract: Total body water (TBW), intracellular (ICW) and extracellular (ECW) spaces, muscle mass and supporting tissue were measured in nine malnourished infants, 5–30 months of age, shortly after hospitalization, and then following 4–9 months of rehabilation. Initially all infants had server growth deficits, heights age being 4–64% (average 40%) and weight age 0–40% (average 15.6%) of chronologic age TBW ranged from 63.5 to 89.3% of body weight and ECW ranged from 38.6 to 50.6% of TBW, suggesting marked losses of cell mass and body fat with conservation of supporting tissues. Excretory levels of creatinine and hydroxproline ranged from 31 to 86 mg/24 h and from 10.3 to 28.5 mg/24 h, respectively. During rehabilitation all patients exhibited accelerated growth, height age becoming 28.6–69.1% (averange 58.8%) of chronologic age; most of the children become moderately obese. With the exception of one infant, who did not gain weight well hydroxyproline increased 45–360% over the intial values. TBW became 54.7–65% of body weight and ECW 41.8–55.9% of TBW. Proportionally smaller increase in metabolically active protoplasm, respresented by ICW, were exprienced in four infants under 11 months (average 25%, than in four of five infants over 11 months of age (average 67.5%); however; these four infants demonstrated proportionately greater gains in ECW (77 versus 36%). Determinations of blood sugar, growth hormone and insulin responses to arginine were made in five of these patients and in three additional infants. On admission, the levels of growth hormone in these infants were found to be elevated (11.5–18 ng/ml) and did not respond, to arginine injection; determination of blood sugar also showed elevated levels (119–182 mg/100 ml). One to three months later the response was usually normal. Insulin responses, initially and after partial rehabilitaion, were almost invariably blunted, with only one child, at 50 days, showing a rise to 45 ng/ml. It is apparent that growth during, recovery from malnutrition is neither a uniform process nor is it simply reinitiation of normal growth. Speculation: The apparently normal production of growth hormone and the impaired insulin, which was persistently demonstrated by these infants, along wiht the poor growth in cell mass of those under 11 months of age, suggest that gains in cell mass in the younger infant may be primarily dependent on insulin and not on growth hormone. Cartilage and other supporting tissues may continue to respond to growth hormone, despite fairly severe malnutririon.

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Robert M. Blizzard

Papers

Micropenis. I. Criteria, etiologies and classification.

Endocrine factors in dental development.

The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases.

Precocious puberty in a boy with hepatoma and circulating gonadotropin.

Infantile Malnutrition: Changes in Body Composition During Rehabilitation