Frank B. Diamond

6 Growth hormone neurosecretory dysfunction

Summary The basis for understanding clinical disorders in the neuroregulation of GH secretion is derived from the complexity of the CNS—hypothalamic-pituitary axis. Studies in animals and humans demonstrate an anatomic, physiological and pharmacological evidence for neurosecretory control over GH secretion including neurohormones (GRH, somatostatin), neurotransmitters (dopaminergic, adrenergic, cholinergic, serotonergic, histaminergic, GABAergic), and neuropeptides (gut hormones, opioids, CRH, TRH, etc). The observation of a defect in the neuroregulatory control of GH secretion in CNS-irradiated humans and animals led to the hypothesis of a disorder in neurosecretion, GHND, as a cause for short stature. We speculate that in this heterogeneous group of children a disruption in the neurotransmitter-neurohormonal functional pathway could modify secretion ultimately expressed as poor growth velocity and short stature.

Is short stature a handicap? A comparison of the psychosocial functioning of referred and nonreferred children with normal short stature and children with normal stature

OBJECTIVES Normal short stature (NSS), defined as height below the 5th percentile for age and sex norms that is not due to illness, hormonal deficiency, or part of a dysmorphic syndrome, has been thought to have a deleterious effect on psychosocial functioning based on observations of referred populations. Recent studies of nonreferred children with NSS, however, have demonstrated normal function. This study directly compared the psychosocial functioning of referred children with NSS, nonreferred children with NSS, and children with normal stature. STUDY DESIGN Participants, 90 children (46 boys, 44 girls) between 6 and 12 years of age (mean, 9. 6 years), were administered intelligence and achievement tests. Parents and teachers assessed adaptive and problem behaviors. Family adaptability and cohesiveness were measured. RESULTS Intelligence and achievement for referred and nonreferred children with NSS were average. Referred children with NSS were reported to have more externalizing behavior problems and poorer social skills than nonreferred children with NSS and children in the control group. Family adaptability and cohesiveness were comparable across groups. CONCLUSIONS Children with NSS have normal psychosocial function, and results suggest that externalizing behavior problems, attention problems, and poor social skills in children referred to clinics for NSS are inappropriately attributed to short stature.

Correlates of adiponectin and the leptin/adiponectin ratio in obese and non-obese children.

Adiponectin is an adipocyte secreted protein that has been reported to increase fatty acid oxidation and improve insulin sensitivity. Our aim was to study the relationship between adiponectin and leptin, body fat, insulin and lipoproteins in obese compared to non-obese children matched for age and gender. Adiponectin serum concentrations were significantly lower in the obese compared to the non-obese children (9.1+/-3.7 vs 17.1+/-12.3 microg/ml, p <0.05), in contrast to serum leptin concentrations which were greater in the obese compared to the non-obese subjects (31.8+/-11.1 vs 8.2+/-5.7 ng/ml, p <0.001). When considered as a single group to assess adiponectin concentrations over a spectrum of body size, adiponectin values correlated inversely with body weight (r = -0.33, p <0.05) and BMI (r = -0.35, p <0.05). Adiponectin values correlated directly with HDL-C (r = 0.47, p <0.005), but not with total cholesterol, IGF-I, or leptin binding activity. Since leptin and adiponectin change inversely in relation to BMI, the leptin/adiponectin (L/A) ratio was determined as a potential index relating adiposity to the development of complications of obesity. The L/A ratio was eight-fold greater in the obese compared to the non-obese children, and correlated more strongly with BMI (r = 0.779, p <0.0001) and with HDL-C (r = -0.53, p <0.001), than did adiponectin alone. The L/A ratio also correlated significantly with triceps skinfold thickness (TSF) (r = 0.77, p <0.001) and percent body fat (r = 0.79, p <0.0001) in non-obese children. These data suggest that adiponectin concentrations are already differentially regulated in childhood obesity. The index of increased leptin concentration corrected by reduced adiponectin values (L/A ratio) merits investigation as a marker for morbidities associated with childhood obesity.

Obesity: the hormonal milieu.

Purpose of reviewObesity has reached epidemic proportions throughout the world and poses significant health and economic burdens to both developed and developing societies. Most recent data from the NHANES study (2003–2004) report that 17.1% of US children are overweight and 32.2% of adults are obese, a significant increase compared with data obtained only 6 years earlier. Recent findingsThe neurohormonal control of appetite, body composition, and glucose homeostasis is mediated by hormones secreted from adipose tissue, endocrine glands, and enteroendocrine cells, which converge at the vagus nerve, brainstem and hypothalamus to modulate complex interactions of neurotransmitters and central appetite-regulating peptides. These hormonal signals are tightly regulated to maintain body weight/adiposity within a narrow, individually defined range that may be further impacted by variables such as ingested calories, meal composition, and lifestyle. SummaryClinical manifestations of obesity, the metabolic syndrome and impaired glucose tolerance reflect biochemical alterations in a complex hormonal milieu. Elucidation of these hormonal perturbations in obese patients has already provided novel pharmacologic treatments to improve weight management and address the metabolic sequelae of obesity. The remarkable redundancy of these hormones, however, and their interactions make a monopharmaceutical approach unlikely to be successful.

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin‐like growth factor I (IGF‐I) during part of a clinical trial. The IGF‐I was given subcutaneously twice daily at a dose of 40 μg/kg on days 1 and 2, 80 μg/kg on days 3 and 4, and 120 μg/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1–7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF‐I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non‐significant glucose and electrolyte changes did not appear to be associated with the cardiac events.

Effects of drug and alcohol abuse upon pituitary-testicular function in adolescent males

To assess the effects of drug and alcohol abuse (DAA) on the physical changes and hormones of puberty in adolescents, 26 males (13 5/12-22 years) enrolled in a drug rehabilitation program were examined. In 22 subjects four timed blood samples were obtained sequentially at 15 minute intervals for measurement of serum concentrations of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and dehydroepiandrosterone sulfate (DHAS). The mean duration of DAA was 3.7 years, with marijuana and alcohol being the most frequently abused substances. The study subjects were compared to a matched control group of non-substance-abusing teenagers. All heights and weights of the DAA subjects fell within two standard deviations of the mean on the Tanner Growth Charts and no statically significant differences in the Tanner stages of sexual maturation were found between the DAA and control groups. The mean (+/- SD) testosterone level of the DAA group (221 +/- 109 ng/dl) was less than half that of the control group (477 +/- 193 ng/dl, p less than 0.001). Mean LH concentration in the DAA group (3.9 +/- 3.0 mIU/ml) was significantly less than that of the control group (10 +/- 4.9 mIU/ml, p less than 0.01). In both the DAA and control populations there was a significant (p less than 0.01) correlation between serum concentrations of LH and testosterone. The mean FSH level of the DAA group (3.3 +/- 1.1 mIU/ml) was significantly less (p less than 0.02) than that of the control group (4.7 +/- 1.9 mIU/ml). To assess the effects of treatment, six boys underwent repeat blood sampling 7-12 months after drug and alcohol withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Leptin and the adipocyte endocrine system

Although adipose tissue has long been considered to be metabolically passive and primarily responsible for energy storage, recent scientific advances have dramatically altered our understanding of the function of this ubiquitous tissue. The fat cell is a transducer of energy supply for the changing metabolic needs of the body, modulating glucose homeostasis, hypothalamic function, sympathetic output, vascular tone, immune response, and reproduction. Through endocrine/autocrine and paracrine actions, adipocyte-derived molecules defend the body during periods of energy deficit and stress. With the development of obesity, maladaptive responses to adipose excess result in pathologic states of inflammation, coagulopathy, and altered insulin sensitivity.

Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: Preliminary results

Auxological and body composition changes were studied in three adolescent patients (2 female, 1 male) with growth hormone receptor deficiency (GHRD) given insulin‐like growth factor I (IGF‐I), 120 μg/kg s.c. twice daily, plus a monthly intramuscular injection of 7.5 mg of a luteinizing hormone‐releasing hormone (LHRH) analogue. Preliminary results from the first 12 months of the study show that height velocity was increased compared with the pretreatment values. This increase was probably due to the IGF‐I therapy, as the LHRH analogue would have suppressed gonadotrophins and gonadal steroid production. There was a reduction in percentage body fat, and increases in lean mass and the leamfat ratio, whole body mineral content and body calcium content, even when expressed per kg body weight. There was also a trend towards increased bone mineral density of the whole skeleton, lumbar spine and femoral structures, as well as a maturation of facial features. These preliminary results indicate that concomitant therapy with IGF‐I and an LHRH analogue is safe and efficacious in inducing growth without advancing bone age in patients with GHRD.

Atypical dendritic cell–related histiocytosis with goiter and primary hypothyroidism

Langerhans cell histiocytosis may be seen with goiter and histiocytic infiltration of the thyroid. We report a 2 1/2-year-old boy who had goiter and primary hypothyroidism develop, later had pulmonary disease, and died of neurologic involvement. Autopsy lesions suggested a transitional dendritic cell precursor of the epidermal Langerhans cell. Of the reported cases of Langerhans cell histiocytosis with goiter in children and adolescents, 82% were male when the relative incidence of Langerhans cell histiocytosis is two males to one female.

Endocrine sequelae of cancer therapy in childhood.

New treatments for neoplastic diseases of childhood have significantly increased patients’ long-term survival and the importance of recognizing and correcting late complications of medical therapy. In this review, we examine both central nervous system (CNS) and non-CNSrelated endocrine morbidities associated with chemotherapy and radiation therapy of childhood cancer. These include effects on growth, puberty, fertility, thyroid and adrenal function which may present many years after the successful treatment of underlying disease.