Band 13, Heft s2 - Supplement

ABSTRACT Continuing growth hormone (GH) replacement therapy in patients with childhood-onset GH deficiency (GHD) that persists into adulthood is an emerging issue. The prospective, long-term metabolic consequences of discontinuing GH therapy in adolescent patients with childhood-onset GHD and short stature have only recently been reported. These studies demonstrate that serum concentrations of total cholesterol, low-density lipoprotein-cholesterol and apolipoprotein В are higher in adolescents in whom severe GHD continues into adulthood. Upon discontinuation of GH therapy, serum concentrations of high-density lipoproteincholesterol have been found to decrease in patients with severe GHD and increase in patients regarded as GH sufficient when retested for GHD. Furthermore, total body fat and truncal fat mass increase after discontinuation of GH in both these patient groups, but more markedly in the patients with severe GHD. In adolescents with severe GHD persisting into adulthood, the discontinuation of GH therapy produces, over a period of 2 years, the accumulation of important cardiovascular risk factors that are associated with GHD in adults. Continuing replacement therapy into adulthood should therefore be considered.

ABSTRACT In order to define the relationship between growth hormone (GH) and peak bone mass, and the importance of the role played by GH in reaching optimal peak bone mass, several questions, discussed in this article, have first to be answered. Although the answers to some of these questions are already becoming apparent, some await the findings of further research. It is doubtful whether the results of these studies, which by definition should be long-term because of the long lag between the end of linear growth and the attainment of peak bone mass, will soon be available. In the absence of evidence-based medicine one can, however, conclude that longterm GH replacement therapy for GH deficiency in adults has no deleterious effects on bone. Indeed, despite an increase in bone turnover and an increase in remodeling space, bone mineral density and bone mineral content have been shown to increase slowly over time and to the same degree in both controlled and uncontrolled studies.

ABSTRACT The optimal treatment of chronic conditions spanning pediatric and adult clinical practice requires the establishment of clear and robust systems for managing the important period of transition of care. This principle is particularly relevant to the treatment of ongoing pituitary dysfunction after the achievement of final height and, in addition to the vital component of maintaining the confidence of the patient, encompasses a number of considerations that are particularly relevant to long-term health as an adult These considerations include the achievement of peak bone mass, optimization of gonadal steroid and glucocorticoid replacement, and determination of the need for continuing growth hormone replacement. It is therefore necessary to consider these issues not only from the standpoint of therapeutic principles but also in the context of practical arrangements for managing the process of transition of care. Successful transition can be achieved using a variety of models, and there is clearly no single preferable option. The most important ingredient in this process is awareness of the situation by both pediatric and adult endocrinologists as well as the development of an agreed strategy within each clinical center.

ABSTRACT In the past decade, a large number of controlled clinical trials have reported positive effects of growth hormone (GH) replacement therapy in GH-deficient adults. The majority of these studies have been carried out in accordance with the guidelines for Good Clinical Practice. The data thus accumulated offer a solid baseline for practicing evidence-based medicine within this area of endocrinology

ABSTRACT Prediction models describing the response of various pathophysiological states to intervention can be of value in confirming a diagnosis, determining the prognosis and promoting compliance with treatment. The rigorous evaluation process of evidence-based medicine, used to assess any diagnostic test or therapeutic intervention, should be applied to studies reporting the development, validation and application of these prediction models. The models can provide only an estimate of the average effect to be expected, so the failure of an individual to exhibit an ‘average’ response does not necessarily imply a problem with that patient. Further development of the models is required to overcome inherent statistical problems and to allow greater applicability to the individual patient.

ABSTRACT Inconsistent and sometimes disappointing final height outcomes in studies in which exogenous growth hormone (GH) was given to children with short stature resulting from various causes have led to attempts to determine the factors that influence responsiveness to GH. Many such factors have been identified, including the genetically determined height potential of the child, the height deficit, current and perinatal auxological and biological factors, and, importantly, GH treatment modalities. These factors vary depending on the cause of the growth failure and during the course of childhood and treatment with GH. Data from welldefined large cohorts can be entered into multiple regression analyses to derive algorithms describing the variation in growth response during a defined period and the influence on this of various factors. Pharmacoepidemiologic surveys have been particularly useful in this regard. Algorithms with low-error SD values, which have included the dose of GH as a variable, can be used to predict the response to a putative GH dose in a similar cohort or in an individual over an equivalent period. A sequential series of such algorithms can be integrated to form a predictive model. Such a model can be used for planning a course of treatment, but the patient data required for entry into the model should be easily obtainable if the model is to have widespread utility. The development of such models will allow GH treatment to be better individualized and optimized for growth and cost outcomes. Growth prediction models will facilitate realistic expectations and will permit stepwise goals to be set and monitored.

ABSTRACT Much has been learned over the past two decades regarding the management of growth hormone (GH) deficiency in children and adolescents. Current GH therapy under ideal circumstances enables children to attain a final height within the normal range and close to their target height However, such a successful outcome is not always achieved and the necessity to individualize treatment according to the specific needs of each GH-deficient child is now well recognized. Consensus does not currently exist as to how to formulate individualized treatment plans. Nonetheless, a clear role for a biochemical, as well as an auxological, monitoring approach has been established. Accurate determinations of height velocity and interval height increase (expressed as the change in height Z-score) continue to be the most important parameters in monitoring the response to treatment. The importance of routinely monitoring serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 is an emerging paradigm. Firm roles have been established for this approach in the assurance of compliance and safety (particularly to avoid long-term theoretical risks). IGF monitoring also has important potential utility as a tool to assess and optimize the response to GH therapy through dose adjustments. In years to come, we expect the development of multiple GH treatment optimization strategies, including approaches such as prediction modeling, as well as serum IGF monitoring and dose adjustments, to evolve and improve.

ABSTRACT The failure of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production represents two of the fundamental pathophysiologic lesions in type 2 diabetes mellitus (DM). Defining insulin action at the molecular level, therefore, provides the critical background against which to elucidate the mechanisms of insulin resistance that underlie type 2 DM, obesity and many other disorders. Over the past two decades substantial progress has been made in identifying many of the molecular mechanisms involved in insulin signaling. Much of this progress has been due to the use of homologous recombinant gene targeting. The present review examines the various insights that have been provided by studies of knockout mice strains. Taken together, the results present the possibility of a unifying hypothesis for type 2 DM, in which insulin resistance in the ß-cell synergizes with insulin resistance in the periphery to produce the two classic defects of this disease: relative hypoinsulinemia and peripheral insulin resistance.

ABSTRACT Type 2 diabetes mellitus (DM) has been considered rare in the pediatric population. However, over the last decade, there has been a disturbing upswing in the rate of diagnosis of type 2 DM in the pediatric age group, mirroring the increasing rates of obesity in childhood. The pathophysiology of type 2 DM discussed in this article focuses on the delicate balance between insulin sensitivity and insulin secretion. The risk factors for youth-onset type 2 DM are presented, with careful evaluation of their impact on insulin sensitivity versus insulin secretion.

ABSTRACT There have been numerous recent reports of case series of type 2 diabetes mellitus (DM) in American Indian, African-American, Hispanic, Asian-American and white children from North America. A similar phenomenon has also been described in several other countries. Prevalence and incidence estimates vary depending on the age and ethnicity of the population, but it is estimated that type 2 DM represents 8-45% of patients with DM currently diagnosed in large US pediatric centers; however, this is likely to be an underestimation and incidence is probably rising. The young patients diagnosed with type 2 DM in the USA were generally overweight, had a strong family history of type 2 DM and often had signs of insulin resistance. The majority belonged to ethnic groups at high risk for type 2 DM. More girls than boys were diagnosed. The few data on follow-up available suggest a high prevalence of microvascular and macrovascular complications among young adults who developed type 2 DM during childhood. Type 2 DM in children has recently been recognized as a potential public health problem in North America. As obesity is currently on the increase in several industrialized or industrializing countries, a similar increase in type 2 DM in children may soon emerge worldwide, and this will require preventative measures.

ABSTRACT The treatment of type 2 diabetes mellitus (DM) is directed at decreasing insulin resistance and increasing insulin secretion. α-Glucosidase inhibitors slow carbohydrate absorption, resulting in reduced postprandial hyperglycemia; thiazolidinediones increase insulin sensitivity, especially in muscle and adipocytes; metformin decreases hepatic gluconeogenesis; sulfonylureas result in prolonged increases in insulin secretion; and meglitinide causes rapid, short-lived increases in insulin secretion. A survey of 130 pediatric endocrinology practices in the USA and Canada indicated that 48% of children with type 2 DM were treated with insulin and 44% with one or more oral hypoglycemic agents (OHA). Of those treated with OHA, 71% received metformin, 46% sulfonylureas, 9% thiazolidinediones and 4% meglitinide. Similarly, in the three university-based diabetes centers in Florida, 50% of the children with type 2 DM were treated with OHA. Treatment is based on symptoms at presentation. Patients identified on routine testing are often treated with exercise and diet alone. Those who are mildly symptomatic at onset are often started on OHA. Patients with substantial ketosis, ketoacidosis or markedly elevated blood glucose levels are initially treated with insulin, followed by a tapering of the dose and the addition of an OHA after blood glucose control is established and symptoms subside. There are no studies of the efficacy or compliance with treatment for type 2 DM in adolescents. Treatment is currently based on the clinical experience with adults. Controlled clinical trials in children are essential.

ABSTRACT The diagnosis of pediatric diabetes mellitus (DM) traditionally is not considered a diagnostic specialty. However, considerable heterogeneity in the etiology of DM is seen among children and adolescents, making the recognition of discrete subgroups of DM very important for determining prognosis and appropriate treatment. The subgroups that result in non-insulindependent DM in children are as follows: the 'honeymoon' phase of type 1 DM, type 2 DM, genetic syndromes accompanied by DM, and maturity-onset diabetes of the young (MODY). The relative prevalence of these different subgroups depends on the population being studied. In the UK, in pediatric clinics where most patients are Caucasian, MODY is over 10 times more prevalent than type 2 DM. However, type 2 DM would predominate in a clinic where most children are from populations with a high prevalence of this condition (e.g. Asian Indians). It should be emphasized that MODY comprises two discrete clinical syndromes: glucokinase diabetes and transcription factor diabetes, the latter of which results from mutations in the genes encoding hepatocyte nuclear factor (HNF)-lα, HNF-lß, HNF-4α and insulin promoter factor-1.

ABSTRACT Dramatically high rates of type 2 diabetes mellitus (DM) have been observed in historically undernourished, recently urbanized populations. A comparable model is the high risk of DM in individuals who were growth restrained in utero and subsequently catch up in size. While it is proposed that undernutrition may somehow adversely program metabolism, both models could also be explained by genotypes that promoted survival during earlier nutritional adversity but later add to the risk of DM. Our recent studies in a contemporary birth cohort have identified two different candidate thrifty genotypes. The insulin gene VNTR ΙII/ΙΙΙ genotype promotes fetal growth and historically could thereby have enhanced survival during infancy. In contrast, the maternally inherited 16189 mitochondrial DNA variant is associated with restrained fetal growth and may therefore enhance the likelihood of maternal survival. Both genotypes are associated with an increased risk of adult type 2 DM in historical cohorts. However, the development of DM in individuals from contemporary birth cohorts may prove to be influenced more by genetic and other early determinants of childhood obesity.

ABSTRACT Clinical studies suggest that estradiol acts as a protective factor in the adult brain. Postmenopausal women suffer from an increased risk of brain injury associated with neurodegenerative diseases such as Alzheimer's disease, and estrogen replacement therapy appears to decrease the risk and severity of this neurodegenerative condition. Studies using animal models show that estradiol exerts similar effects in rodents and can enhance cell survival. Therefore, we designed experiments to determine whether estradiol treatment can decrease brain injury induced by an experimental model of ischemia. Our experiments used a permanent middle cerebral artery occlusion model and physiological levels of estradiol replacement therapy. The results demonstrate that estradiol exerts profound protective effects against ischemic brain injury induced by cerebral artery occlusion and that this protective action correlates with changes in the level of gene expression of estradiol receptors and members of the Bcl-2 family. These data suggest that estrogen replacement therapy may provide important protection against age- and diseaserelated degenerative processes in the brain.

ABSTRACT The metabolic consequences of reaching full reproductive maturity in humans involve not only growth hormone (GH) and insulin-like growth factor-I, but also the collaborative interaction of the gonadal sex steroids. Estrogen is critical for completing linear growth. It also inhibits bone resorption, decreases plasma lipid levels and serves as an antiatherosclerotic agent. Our studies show that, in low doses, estrogen increases GH production, increases calcium absorption and decreases bone turnover; however, unlike testosterone, estrogen has no effects as a protein-anabolic agent, at least at the whole body level. Studies of selective estrogen suppression, achieved using a potent aromatase inhibitor, show that estrogen is the main regulator of the gonadotropin axis. In boys, selective aromatase blockade may have a role in delaying epiphyseal fusion. Large placebo-controlled trials will be required to study this effect further.

ABSTRACT The discovery of a man with a homozygous mutation in the estrogen receptor α gene, which results in estrogen-receptor α resistance, and of males and females with autosomal recessive mutations in the CYP19 gene encoding aromatase, which leads to a failure to synthesize estrogens, has challenged conventional wisdom about the 'unimportant' role of estrogen in the male. For example, in the male, estrogen (not androgen), derived from direct testicular secretion (~20%) and from extragonadal aromatization of testosterone and androstenedione (~80%), is the critical sex hormone in the pubertal growth spurt, skeletal maturation, accrual of peak bone mass, and the maintenance of bone mass in the adult. Estrogen stimulates chondrogenesis in the epiphyseal growth plate increasing pubertal linear growth. At puberty, estrogen promotes skeletal maturation and the gradual, progressive closure of the epiphyseal growth plate, possibly as a consequence of both estrogen-induced vascular and osteoblastic invasion and the termination of chondrogenesis. In addition, during puberty and into the third decade, estrogen has an anabolic effect on the osteoblast and an apoptotic effect on the osteoclast, increasing bone mineral acquisition in axial and appendicular bone. In the adult, estrogen is important in maintaining the constancy of bone mass through its effects on remodeling and bone turnover. Establishing a role for estrogen does not exclude a direct action of testosterone on bone in the human male (especially on cortical bone), but this action is less characterized than thought in the past and is relatively minor in comparison with the major effect of estrogen in the male.

ABSTRACT The route of estrogen replacement therapy has a major impact on the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. Estrogen administration by the oral, but not the transdermal, route reduces IGF-I and increases GH levels in postmenopausal women. This perturbation of the GH-IGF-I axis occurs with different forms of estrogen treatment, indicating that the dissociation of the somatotropic axis and concomitant increase in GH-binding protein levels are intrinsic effects of the oral route of estrogen administration. In clinical studies, oral estrogen reduced postprandial lipid oxidation, compared with transdermal estrogen. Oral estrogen was also associated with a reduction in lean body mass and an increase in fat mass, compared with transdermal estrogen. In contrast, the route of estrogen therapy had no impact on carbohydrate metabolism or the estrogen-induced increase in bone mineral density. The findings of route-dependent changes in body composition add a new dimension to health considerations concerning estrogen therapy in postmenopausal women and may have significant implications for estrogen replacement therapy in young hypogonadal females.

ABSTRACT The aging process has multiple causes. However, there is now substantial evidence consistent with the hypothesis that (i) all normal mammalian somatic cells have a finite capacity to replicate and (ii) that gradual cell turnover throughout the lifespan of a mammal eventually exhausts this finite capacity. This results in a gradual accumulation of senescent (irreversibly post-mitotic) cells with increasing age. These cells display a radically different phenotype to their growing counterparts, which has the potential to compromise tissue function. Perhaps the best evidence for this is seen in Werner’s syndrome, a rare genetic disease, in which patients display most of the features of accelerated aging, together with a profoundly compromised replicative lifespan in certain tissue lineages. Several classes of human cells are now known to count divisions by monitoring the progressive attrition of chromosomal ends (telomeres), leading to the activation of a p53-p21 waf - dependent G1 checkpoint. Ectopic expression of telomerase has been shown to prevent senescence in several cell types and offers the potential for interventions in the aging process based on tissue engineering, gene therapy or homeografts. However, this telomere-driven senescence mechanism seems to be absent from rodents, which use telomere-independent means (perhaps based upon p14 arf ) to count divisions. Similar senescence pathways are now being reported in humans, and this, coupled with the demonstration of tissue-specific telomeric loss rates, has the potential to render strategies based on the use of telomerase dependent on the characteristics of the target tissue. Werner’s syndrome may provide strong clues regarding the potential limitations and prospects of such future treatments.

ABSTRACT The notion that all aging is ultimately cell aging is a novel hypothesis and one with growing support. Recent studies in genetics and cell biology are consistent with this view. Criticism of the model is largely reflective of inadequate understanding of both the model itself and human pathology. Hutchinson-Gilford progeria is a segmental progeria that may well be an 'epigenetic mosaic' disease in which certain cell lines exhibit early cell senescence, while others are spared. The general cell senescence model of aging offers a consistent and elegant explanation of both human aging and progeria. More importantly, the model is not only testable but implies fundamental, novel and promising therapeutic avenues for both progeria and more typical age-related diseases.

ABSTRACT This review article discusses the roles of the somatotropic axis in the growth and development of the normal central nervous system (CNS) and during recovery from brain injury. Classically, the actions of pituitary-derived growth hormone (GH) have been reported to be primarily mediated via the induction of hepatic insulin-like growth factor-I (IGF-I). GH receptors (GHRs), however, have now been identified in many body tissues and shown to have both endocrine and local actions, some of which are IGF-I independent. Within the brain, GHRs are widely located across a range of cellular phenotypes, yet little is known regarding their function or endogenous ligand. It is now becoming accepted that GH, like IGF-I, is integrally involved in the growth and development of the normal CNS. Following brain injury, IGF-I mRNA is induced, primarily within reactive microglia. The resultant IGF-I protein appears to have a dual role, first as an endogenous neurotropic and anti-apoptotic agent acting directly on stressed cells, and second as a prohormone for generation of the N-terminal tripeptide of IGF-I, glycine-proline-glutamate (GPE), and the resulting des-N-(l-3)-IGF-I, both of which have specific neuroprotective properties. Our work on deciphering the upstream regulators of injury-induced IGF-I has revealed that a GH-like substance is strongly upregulated after brain injury and specifically associated with stressed neurons and glia. Subsequent to this finding, GH administered centrally 2 hours after a hypoxic-ischemic brain injury in juvenile rats was found to provide significant neuroprotection, interestingly, in a spatiotemporal pattern distinct from the neuroprotection offered by IGF-I. The implications of these findings in regard to the growth, development and injury response of the CNS are discussed.

ABSTRACT The activity of the growth hormone (GH)- insulin-like growth factor-I (IGF-I) axis undergoes marked variations across the human life span, mainly reflecting age-related changes in the neural control of somatotroph function. IGF-I secretion generally reflects GH status, except in newborns, who secrete high levels of GH but low levels of IGF-I. Changes in the gonadal steroid milieu, particularly estradiol, play a major role in the enhanced activity of the GH-IGF-I axis at puberty and probably reflect further changes in the neuroendocrine control of somatotroph secretion. The change in responsiveness of somatotrophs to various stimuli, including GHRH, is not as marked as the spontaneous secretion of GH at puberty. However, in childhood, somatotrophs are unusually refractory to the somatostatin-mediated negative GH autofeedback mechanism. Normal children show normal responsiveness to the stimulatory influence of α-adrenergic and cholinergic agonists, galanin and arginine, but the activating effect of these stimuli on somatotroph secretion is reduced in elderly individuals, with the notable exception of arginine. Arginine potentiates both spontaneous and GHRH-induced GH secretion to the same extent in normally growing children, adults and elderly individuals, indicating that the releasable pool of GH is generally preserved across the human life span. Thus, the reduction in spontaneous and GHRH-induced GH secretion in the elderly probably reflects age-related changes in neurotransmitter control, leading to GHRH hypoactivity and absolute or relative somatostatin hyperactivity in the aged hypothalamus. Cholinergic impairment in the aging brain probably involves hypothalamic pathways and leads to decreased activity of the GH-IGF-I axis in normal and elderly individuals, as well as in individuals with premature brain aging. However, there is evidence indicating that age-related variations in the activity of the natural GH-secretagogue ligand(s) at the hypothalamic level could also play a role in the age-dependent changes in the GH-IGF-I axis.

ABSTRACT Under the influence of testicular secretion, the male vocal cords increase in length by 67% in adult men compared with prepubertal boys, whereas in the female the increase is only 24%. This greater length and an increase in vocal cord mass is responsible for the lowering of pitch of the male voice during puberty. From the late 16 th century, castration was carried out in Italy to preserve the unbroken male voice into adult life, but the high pitch was accompanied by fully grown resonating chambers and a large thoracic capacity, giving rise to the unique voice of the castrato. The initial stimulus for the production of castrati came from the Sistine Chapel in Rome, to provide singers for the complex church music of the time. The second reason was the coming of opera to Italy at the beginning of the 17 th century. Boys were castrated between the ages of 7 and 9 years, and underwent a long period of voice training. A small number became international opera stars, of whom the most famous was Farinelli, whose voice ranged over three octaves. By the end of the 18 th century, fashions in opera had changed so that the castrati declined except in the Vatican, where the Sistine Chapel continued to employ castrati until 1903. The last of the castrati was Alessandro Moreschi, who died in 1924 and made gramophone recordings that provide the only direct evidence of a castrato’s singing voice.