How to Grow Taller

Grow Taller Dynamics

Doctor Philip Miller come up with this awesome product to help people gain extra height naturally without the need for surgical methods. He is a professional doctor with specialization in Neurosurgery. He got the inspiration to research and come up with this program from her daughter who was having a hard time with her boyfriend simply because she was short. It comprises of all the methods that you can use to increase the production of Human Growth Hormone which includes exercise and the intake of amino acids. The program is available in downloadable eBooks that has step-by-step guide on what to do and impact your height naturally. The pogram was developed after a comprehensive research by Dr. Phillip Miller on the scientific base of human developement. This means that the product has a strong scientific base. For this reason, you can be assured that all the things and techniques demonstrated on the product are reliable. There are no side effects recorded throughout this period and hence the program is safe and effective. Dr. Miller uses simple language to write the details of this program and hence you can be sure that you will get every detail. The product is for all people regardless of their gender, race and finacial ability. Read more here...

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Modeling The Pituitary Release Of Growth Hormone

For the growth hormone system, the pituitary modifies the hypothalamic output and any exogenously applied stimulation with hormone releasing peptides to such an extent that, if the authors wish to infer the output of the hypothalamus from the observed profile of GH in the circulation, then as a first step they must establish a mathematical model that adequately reflects the behavior of the pituitary. A preliminary model has been based (13) on the Law of Mass Action applied to reversible binding of GRF and or secretagogue to its receptors (Fig. 1). For the present the general discussion will be phrased just in terms of GRF. However, in general, analogous arguments hold for the actions of GHRP and other artificial secretagogues at the pituitary when these are applied in isolation, so the following model framework can be extended naturally to encompass these additional factors. How to model the pituitary response to simultaneous application of GRF and artificial secretagogues is beyond...

The Growth Hormone Family of Hormones and Receptors

Growth hormone (GH), placental lactogen (PL), and prolactin (PRL) regulate an extensive variety of important physiological functions. While GH biology generally centers around the regulation and differentiation of muscle, cartilage, and bone cells, it is the PRL hormones and receptors that display a much broader spectrum of activities, ranging from their well-known effects in mammalian reproductive biology to osmoregulation in fishes and nesting behavior in birds 1 . Within the cytokine superfamily, the growth hormone (GH) prolactin (PRL) endocrine family of hormones and receptors is arguably the most extensively studied system focused on structure-function issues and molecular recognition 2-6 . These studies and those of related cytokine systems have been instrumental in defining modes of hormone action and regulation 7-12 . The structure-based mechanisms by which these systems activate are similar 4,6,7 however, although these mechanisms are conceptually simple (hormone induced...

Structure of Human Growth Hormone

Although little sequence identity exists among members of the hematopoietic cytokine family, most have either been shown or predicted to be four-helical bundles (3). The four-helix bundle structural motif was first described with the crystal structure for the porcine growth hormone (6). In the case of hGH, the four-helical bundle topology was first observed in the crystal structure of the hGH-hGHR complex (7). Hormones belonging to this group can be subdivided into two general classes called short-chain and long-chain. hGH is classified as a long-chain helical cytokine because of the length of each of the helices (between 21 and 30 amino acids). All members of this cytokine group are characterized by an antiparallel up-up-down-down arrangement of the helices. This helical organization requires rather long extended loops between helices 1 and 2 and helices 3 and 4 (Fig. 1). In hGH, helices 1 and 4 are longer (26 and 30 residues) than helices 2 and 3 (21 and 23 residues).

The Hypothalamic PituitaryGrowth Hormone Axis

During childhood or adolescence may result in chronic GH suppression and subsequently, psychosocial short stature. However, with amelioration of environmental conditions during development, this may be reversed (Gohlke et al, 2004). Also Anorexia nervosa coincides with dysreg-ulation in GH-IGF-1 functioning and, given a prepubertal disease onset, may result in diminished final body height (Munoz and Argente, 2002).

Growth Hormone Deficiency

Early studies showed that a significant proportion of growth hormone deficient (GHD) children respond to the acute administration of GHRH with a rise in GH levels (20-22). These responses are lower on average than those of normal children or non-GH deficient children with short stature, but can overlap into the normal range (Fig. 4) (21). Depending The situation is different in adults with acquired GHD, most of whom have pituitary disease or iatrogenic pituitary damage. In this setting, GHRH cannot be used for treatment, but the absence of a GH response to GHRH can be used as a diagnostic test for GHD, particularly in combination with the simultaneous administration of arginine to reduce the blunting of GH responses by age or obesity (42). The combined GHRH-arginine test is one of the diagnostic tests recommended by the Growth Hormone Research Society consensus workshop (54).

Changes In Growth Hormone And Insulinlike Growth Factor1 In Hiv Infection

Disturbances in the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis have also been described in HIV infection. Decreased levels of IGF-1 have been noted in some malnourished individuals with HIV infection (37,38), but normal levels of IGF-1 were reported in two other groups of patients with prior weight loss (30,39). One potential explanation for these discrepant findings is that the patients in these latter two groups were studied during periods of relative clinical and weight stability, whereas the two former groups included patients who were losing weight at the time of study. Frost et al. (38) noted a pattern of increased serum GH levels, coupled with decreased IGF-1 levels in 3 of 11 patients with HIV-associated wasting. On the other hand, in a recent study of GH secretory profiles in patients with HIV infection, growth hormone deficiency was evidenced by decreased GH peak amplitude and area under the curve (40). Evidence of growth hormone resistance has been...

And Growth Hormone

Epinephrine,the glucocorticoids, thyroxine, and growth hormone stimulate the catabolism of carbohydrates and lipids.These hormones are thus antagonistic to insulin in their regulation of carbohydrate and lipid metabolism.Thyroxine and growth hormone promote protein synthesis, however, and are needed for body growth and proper development of the central nervous system.The stimulatory effect of these hormones on protein synthesis is complementary to that of insulin. The anabolic effects of insulin are antagonized by glucagon, as previously described, and by the actions of a variety of other hormones. The hormones of the adrenals, thyroid, and anterior pituitary (specifically growth hormone) antagonize the action of insulin on carbohydrate and lipid metabolism. The actions of insulin, thyroxine, and growth hormone, however, can act synergis-tically in the stimulation of protein synthesis. Growth Hormone The anterior pituitary secretes growth hormone, also called so-matotropin, in larger...

Contemporary Endocrinology

Sports Endocrinology, edited by Michelle P. Warren and Naama W. Constantini, 2000 22. Gene Engineering in Endocrinology, edited by Margaret A. Shupnik, 2000 21. Hormones and the Heart in Health and Disease, edited by Leonard Share, 1999 20. Endocrinology of Aging, edited by John E. Morleyand Lucretia van den Berg, 2000 19. Human Growth Hormone Research and Clinical Practice, edited by Roy G. Smith

Why Measurements Are Useful

Most syndromes with dysmorphic features show disturbances of growth either of the entire body or of certain body parts. In the past, various unusual features have been expressed in qualitative terms such as short stature, long fingers, or other terms that imply a comparison with other body proportions. An impression of the patient or a gestalt is formed in the reader's mind. The more objective way to assess body proportions is by quantitative measurement. This is especially important when the disturbance in growth involves only a specific body area or can be related to a disease process, because it may give insight into the basic mechanisms underlying the growth disturbance and thus the pathogenesis of the disease.

Useful Parameters and Landmarks

When length, weight, or head circumference deviate from the normal growth curve, further investigation is warranted. Many different pathological processes, some of which may be treatable, can lead to growth failure. Discrepancies in growth proportions may provide clues to the pathological process for instance, chronic infection and renal failure lead to relative loss in weight, while growth hormone deficiency and Cushing syndrome produce relative increase in weight. Usually, by two years of age a child has established a pattern of growth that will predictably follow percentile growth curves. These growth curves, on average, are similar for OFC, height, and weight. During the first year of life a child may change percentile growth curves as he or she establishes an extrauterine growth pattern.

Thermodynamic Mapping of Antigen Antibody Interfaces

On the basis of extensive mutational analysis of the complex between human growth hormone and its receptor, Wells and colleagues 24-26 proposed that the formation of specific protein-protein complexes is mediated by only a few productive interactions or hot spots that dominate the energetics of association. Consistent with this idea, our analysis of the D1.3-HEL interaction revealed that only a small subset of the total combining site residues of D1.3 appears to account for a large proportion of the binding energy most residues (9 of 14) make little or no apparent net contribution (1.0 kcal mol), even though a number of hot spots (AAG 2.5 kcal mol) are clearly present. Therefore, stabilization of the D1.3-E5.2 complex is achieved by the accumulation of many productive interactions of varying strengths over the entire interface between the two proteins. To investigate the apparent contribution of E5.2 residues to stabilization of the D1.3-E5.2 complex, single alanine substitutions were...

Applications Of Microarrays To Agingrelated Research

Several studies have reported gene expression profiles corresponding to long-lived mammalian models, as a result of environmental changes such as calorie restriction (CR) (Park and Prolla, 2005b), as well as longevity-enhancing mutations, such as the Ames dwarf, the growth hormone receptor knock-out (GHR-KO) (Dozmorov et al., 2001 Miller et al., 2002 Tsuchiya et al., 2004), and the fat-specific insulin receptor knock-out (FIRKO) (Bluher et al., 2004). In C. elegans, the transcriptional changes associated with longevity-determining mutations in the insulin-like IFG-1 pathway have been well characterized by microarray, resulting in the identification of several previously unknown aging genes (McElwee et al., 2003 Murphy et al., 2003).

Transformation via Competent Cells

Although the characteristics of competent cell transformation, i.e., the DNA taken up being small in size and single stranded, are extremely useful for mapping studies and chromosomal manipulation, they hamper the transformability of Bacilli with ligation mixtures. Because of the paring of the DNA at the binding stage, monomeric plasmids, as well as ligation mixtures, cannot be used to successfully transform B. subtilis-competent cells (Canosi et al., 1978). Only plasmid multimers, either present in the preparation from most E. coli strains or generated in vitro via ligation (Mottes et al., 1979) or via polymerase chain reaction (Shafikani et al., 1997), can efficiently transform Bacillus. This is a major obstacle to the preparation of random plasmid libraries directly in this organism. One must first prepare the libraries in E. coli and then transform Bacillus with such libraries. One of the major drawbacks to this approach is the possible toxicity to E. coli often exhibited by genes...

Current Status Of Peptide Agonists For Cytokine Receptors

Many recombinant cytokines are successfully marketed as drugs, including recombinant forms of human growth hormone (hGH), EPO, G-CSF, interferon (IFN)-a, IFN-P, interleukin (IL)-2, and IL-11 (44). Others are in late stages of clinical development. Scientists have been searching for smaller peptide cytokine agonists that mimic the activity of their larger counterparts to use as probes for understanding the detailed mechanisms of receptor activation. EPO mimetic peptide 1 (EMP1) was the first reported peptidomimetic (45). Subsequently, small-peptide agonists of the EPO and TPO receptors, including the EMP1-related peptides AF13948 (46), PK1 (47), and GW395058 (48), were reported.

Review of evidence for a genetic effect

High values of Is or heritability provide summary evidence for a large total genetic effect but can be consistent with low individual locus or variant specific heritabilities and thus low detectance and study power if many loci or variants contribute to the genetic effect (as may be the case with adult height) (Figure 6.1). If there has been a lack of success in adequately powered linkage studies despite high Is values, it suggests that each individual variant accounts for only a low proportion of the total genetic effect.

Signaling at Periplasmic Ligand Binding Domain

In contrast to many other receptors, such as growth hormone receptors, bacterial chemotaxis receptors do not signal by horizontal aggregation of the receptor monomers instead, ligand binding induces small conformational changes, which are assumed to be transmitted through the transmembrane helices to the cytoplasmic domain and to affect the phospho-rylation rate of the bound histidine kinase (recently reviewed by Falke and Hazelbauer 29 ). Crystal structures of the ligand binding domain of a Salmonella tryphimurium aspartate receptor (Tar) mutant 22 in apo and liganded (Asp bound) forms and of the wild-type Tar of apo and liganded forms 30 revealed one Asp bound per dimeric receptor, which was also shown to be true in solution 31 . The difference distance matrix method of comparing apo and Asp bond forms

Functions Of Srif Receptor Subtypes

Pharmacological studies have suggested that sstr2 is involved in mediating the inhibition of GH release by SRIF (14,15). The rank order of affinities of a large series of SRIF analogs to bind to cloned mouse sstr2 was similar to their rank order of potencies to inhibit GH release from rat pituitary cells in culture. In contrast, there was no clear correspondence between binding to the other receptors and inhibition of GH release. sstr2 mRNA and protein, as detected by immunoblotting are expressed in the anterior pituitary (1,20,21) consistent with the role of this receptor in controlling growth hormone secretion.

Structural Basis for Receptor Homodimerization

Tertiary structure plays a role in how the hormone regulates receptor activation. The hormones in this family are long chain four a-helix bundle proteins 4,17 . A notable feature of their tertiary structure is that it contains no symmetry that might support equivalent binding environments for the receptors. How the two receptors bind to the asymmetric hormone was first revealed from the crystal structure of human growth hormone bound to the extracellular domain (ECD) of its receptor (hGH-R) 8 . The structure showed that the two ECDs binding to site 2 and site 2, respectively, use essentially the same set of residues to bind to two sites on opposite faces of the hormone 8 (Fig. 1). An identical model is seen in a prolactin hormone-receptor complex 18 . This binding is characterized by extraordinary local and global plasticity at the binding surfaces. The two binding sites have distinctly different topographies and electrostatic character, leading to different affinities for the...

Hormone Specificity and Cross Reactivity Determine Physiological Roles

Binding to the two structurally distinct sites on the hormone, while using the same binding determinants, requires the receptor binding surfaces to undergo significant local conformational change 8,18 . The structural requirement is further expanded by specificity factors 9 . The biology of pRL and GH is integrated on many levels 20 however, over the 400 million years since pRL and GH diverged from a common gene parent, evolution has built in different regulating components distinguishing them 21,22 . In primates, the growth hormone receptor (GH-R) is activated solely by homodimerization through its cognate hormone 8,21 , but prolactin biology works through regulated cross-reactivity. Most PRL-R receptors are programmed to bind both prolactin and growth hormone 23 .

Receptor Receptor Interactions

A conserved structural element of the ligand-induced homodimerization of prolactin and growth hormone receptors is a set of extensive contacts between their C-terminal domains. This receptor-receptor interface was described in detail for the hGH hGH-R 1 hGH-R2 ternary complex 3,8 and modeled for the hGH-hPRL-R ternary complex 3 . Although the topology of the C-terminal domains of the rPRL-R is virtually identical to that of the C-terminal domain of hGH-R, the receptor-receptor interfaces in these two complexes show a marked variation in their orientation and electrostatic character, and different portions of the receptors are involved in the interaction. The surface area buried in the interaction between rPRL-Rs is smaller than that buried between hGH-Rs the former being 370 A2 compared to 470 A2 for the latter.

Biological Implications of Transient Receptor Dimerization

Functional and structural information suggests that the role of receptor homodimerization is more complicated than simply bringing the cytoplasmic elements of the receptors together. For instance, structural studies of erythropoietin (EPO) and its receptor (EPO-R) indicate that a function of the hormone is to establish a fairly exact receptor alignment, as well as to induce dimerization 33-36 . Based on patterns of cross-hormone and cross-species activities and the known structural differences in the active complexes, exact receptor orientation is probably not as crucial for prolactin and growth hormone systems.

Smith Magenis Syndrome

SMS (MIM 182290) is a multiple congenital anomalies and mental retardation disorder associated with an interstitial deletion within chromosome 17p11.2 (10-13). Clinical characteristics include minor craniofacial and skeletal anomalies such as brachycephaly, frontal bossing, synophrys, midfacial hypoplasia, short stature, and brachydactyly, neurobehavioral abnormalities such as aggressive and self-injurious behavior and sleep disturbances, ophthalmic, otolaryngological, cardiac, and renal anomalies (13,14).

Value of Simplicity in a Pituitary Model

Much more complex models of this system could be constructed, and for some stages, many detailed models already exist. For example, there are a number of models describing intracellular calcium fluctuations in response to agonists applied in the extracellular environment (15,16). Models are also available of the exocytosis of hormone or neurotransmitter in response to a rise in intracellular calcium (17). Therefore, it would be possible, to assemble these models into an overall model describing somatotroph growth hormone output as a function of GRF or artificial secretagogue stimulation. This would still leave the inhibitory input of SRIF and its interaction with GRF to be included. However, the resulting complete model would be very complex. Goldbeter (18) discusses a four differential equation model for the response of pituitary cells to luteinizing hormone-releasing hormone, which is essentially a more complex version of the authors' model here (without any somatostatin terms). The...

Anthropometric Factors

The data on breast cancer risk and height have been relatively consistent in demonstrating an increase in risk with increased adult height. A pooled analysis of seven prospective cohort studies of height and breast cancer risk reported relative risks for breast cancer, after adjusting for other risk factors, of 1.02 per 5 cm of height among premenopausal women 95 confidence interval (CI) 0.96-1.10 and 1.07 among postmenopausal women (95 CI 1.03-1.12).29 The relationship between greater height and risk of breast cancer is hypothesized to be due to the influence of growth hormone, insulin-like growth factor-I (IGF-I),30 or possibly in utero influences on ductal stem cells.31

A tragedy in the making

That was the context in which certain types of dwarfism began to be treated with growth hormone extracted from human pituitary glands. The role of the pituitary in the body's growth had been demonstrated in 1916, when experiments showed that removal of the pituitary from tadpoles halted their growth, and that this could be corrected by injecting pituitary extracts. A few years later, in 1921, other researchers showed that injecting cow pituitary extracts into rats caused gigantism and that removal of the pituitary from dogs would halt their growth. It seemed reasonable to conclude that a pituitary hormone stimulated growth. Scientists purified the hormone using the pituitaries of various animals, testing the ability of the different extracts to stimulate growth in rats whose pituitaries had been removed. This growth hormone, known also as somatotropin, turned out to be a protein made up of a chain of 191 amino acids. Human growth depends on many genetic and environmental factors. For...

Darchone Chow Lena Brevnova Xiaolin He and K Christopher Garcia

The gp130-cytokine system has been the subject of extensive protein structure-function studies aimed at elucidating the basis of ligand recognition and receptor activation. A longstanding question has been the architecture of the higher order signaling assembly. It is clear from functional studies that the paradigm of gp130-cytokine recognition will differ substantially from the classical homodimeric systems typified by human growth hormone and its receptor. Recently, the crystal structure of a viral interleukin-6 (IL-6) complexed with the D1, D2, and D3 domains of the gp130 extracellular domain has reconciled much of the functional and mutagenesis data that exist for a variety of gp130-cytokine systems. The topology of the viral IL-6-gp130 assembly also appears to satisfy the structural requirements of an analogous signaling complex of granulocyte colony-stimulating factor (GCSF) and its receptor. A previous crystal structure of an inactive form of this complex can be supplanted by a...

The Insulin Like Growth Factor Family

Levels of circulating IGF-I change substantially over time. Expression of the IGF-I gene is regulated primarily by growth hormone, and IGF-I in creases slowly from birth to puberty, surges at puberty, then declines with age.64 In addition to growth hormone, estrogen and other hormones, tamoxifen, and oral contraceptives interact with members of the IGF family and influence IGF expression in breast tissue.64. Animal studies have suggested that dietary factors may induce different patterns of IGF-I transcription, and energy restriction has also been shown to modulate circulating IGF levels. Anthropometric factors, physical activity, alcohol, and smoking have been reported to affect the level of IGF-I, although much of the evidence is weak.64

Receptor Ligand Interactions

Although many different cytokine systems exist, a relatively restricted set of topological solutions is utilized by the different families to assemble higher order signaling complexes. The most basic building block is the interaction of the cytokine helical faces with the receptor cytokine-binding homology regions (CHRs), as typified by the human growth hormone (hGH) and erythropoeitin (EPO) examples, among others 1-5 . This interaction is a universally conserved recognition module that is then utilized in different geometries by various cytokine systems. The majority of cytokines require hetero-oligomerization of cytokine-specific receptors with shared signal-transducing receptor(s) 6 , so the structural basis of receptor activation is quite different from the simpler homodimeric systems.

Scf Gene And Protein Interactions Between Scf And cKit

Thus SCF, M-CSF, and Flt3 ligand are members of the large family of four-helix bundle proteins. The 4-helix bundle family has three subtypes short chain, with relatively short a-helices long chain, with relatively longer a-helices such that the overall 4-helix bundle structure is more elongated and interferon (IFN)-like (27). Many family members, growth hormone being a well studied example, are ligands for receptors of the hematopoietin receptor family (27). These receptors do not have intrinsic kinase activity, but dimerization is necessary for the initiation of intracellular signaling. In the growth hormone growth hormone receptor-binding paradigm, separate regions of monomeric ligand interact with similar regions of two receptor molecules to mediate receptor dimerization (27,28).

Alanine Scanning Mutagenesis of the hGHR

The receptor also contains a centralized functional epitope surrounded by a number of hydrophilic residues that are generally less important for binding. Once again, it has been suggested that the nonfunctional, charged residues surrounding the very hydrophobic binding site are probably responsible for promoting solubility and specificity (27). In fact, it has been demonstrated that a single arginine residue (R43) in the extracellular domain of the hGHR contributes significantly to species specificity for growth hormone binding (28). Taken together, both of these mutational studies (on hGH and hGHR) clearly demonstrate that only a small subset of contact residues are important for modulating the energetics of binding.

Intracellular Events Transmitted Following Formation Of The Hghhghr2 Complex

A number of studies using various cell lines have shown that hGH stimulates tyrosine phosphorylation of the hGHR intracellular domain, the JAK2 intracellular protein kinase, and several STAT proteins (34-36). It has also been demonstrated that JAK2 directly interacts with the hGHR (37). Following hGH-induced receptor dimerization, JAK2 rapidly phosphorylates itself as well as specific tyrosine residues on the receptor and on STAT (Fig. 6). STATs 1, 3, and 5 have all been implicated in the growth hormone signaling pathway (38,39). Even though the intracellular domain of the hGHR is also phosphorylated, mutation of the phosphotyrosine residues does not affect proliferative signaling or JAK2 STAT activation (40).

Ligand Receptor Complexes

The TNF-P-TNF-R1 interaction involves two separate contact regions (Fig. 2b) corresponding to the second and third CRDs of TNF-R1 which bind to protruding polypeptide loops of TNF-p. The recently determined structure of the TRAIL receptor bound to its ligand reveals a similar mechanism of engagement 18,19 . Complexes of other members of the TNF-R family with their ligands are likely to exhibit a similar mode of binding. However, the putative ligand (and receptor) binding regions of homologous receptors and ligands share no apparent sequence identity. This is true even of TNF-R1 and TNF-R2, which recognize the same ligands, and of TNF-a and TNF-P, which bind to the same receptors 10 hence, the same binding surfaces must perform two different recognition functions. Human growth hormone receptor binds both prolactin and growth hormone, and the structures of its complexes with the two ligands reveals one solution to the dual specificity problem 33 .

Transgenic Mini Rat Strain as a Tool for Studying Aging and Calorie Restriction

Mini rats, a transgenic strain of rats whose somatotropic axis was suppressed by overexpression of the antisense growth hormone gene, were shown to live longer than nontransgenic wild-type rats ( ), when heterozygous for the transgene (tg ) homozygous (tg tg) rats died slightly earlier due to neoplastic causes. As observed in (tg ) rats, moderate suppression of the somatotropic axis produced some phenotypes similar to those in ( ) rats subjected to calorie restriction (CR), a well-known experimental intervention favoring longevity in animals. Thus, comparative studies using (tg ) rats with the CR paradigm will help us understand the role of the somatotropic axis in regulation of lifespan and aging. Furthermore, the level of suppression of the somato-tropic axis in (tg ) rats was not as severe as in other mice models, and thus, experiments can be performed within physiological ranges. In the last decade, since Ames dwarf mice with spontaneous mutation of the prop-1 gene were reported...

Where Are Ghrs Expressed

Recent in situ hybridization studies have provided information on the specific distribution of GHR gene expression. In most species so far investigated, the main neural sites of expression of GHR in the CNS of adult animals are in the hypothalamus and hippocampus with the majority of studies carried out in the rat (Fig. 1). Within the hypothalamus, there is increasing evidence that GHRs are involved in a short loop feedback regulating GH secretion. Initial studies from Burton et al. (18) localized GHR expression to periventricular nucleus (PeN) somatostatin (SRIF) neurons, consistent with a feedback loop increasing SRIF expression and release in the face of high GH expression. GHR transcripts were also found in the arcuate nucleus (ARC) consistent with the idea that GH feedback inhibits growth hormone releasing hormone (GHRH) expression. Although ARC GHR expression is present in a small number of GHRH-containing neurons (19), the majority of ARC GHR-expressing cells also express...

Extension in the Dwarf

Dwarf mice are remarkably long-lived. Congenital deficiency of growth hormone (GH), prolactin, and thyroid-stimulating hormone (TSH) due to mutations at the Pit1 or Prop1 loci, as well as GH resistance due to targeted disruption of the GH receptor gene lead to major increase in both average and maximal lifespan. Prolonged longevity of Snell dwarf (Pit1dw), Ames dwarf (Prop1df), and GHRKO mice is associated with a major extension of ''health span'' and multiple symptoms of delayed aging. Suspected mechanisms of prolonged longevity of hypopituitary and GH resistant mice include reduced peripheral levels of IGF-1 and insulin, enhanced sensitivity to insulin actions, reduced generation of reactive oxygen species, enhanced anti-oxidant defenses and stress resistance, and delayed onset of fatal neoplastic and nonneoplastic disease. Although negative correlation of body size and longevity applies to genetically normal mice and to other species, it remains to be determined whether reduced GH...

Chemical Classification of Hormones

Polypeptide hormones generally contain less than 100 amino acids an example is antidiuretic hormone (table 11.2). Protein hormones are polypeptides with more than 100 amino acids growth hormone is an example. The distinction between polypeptide and protein hormones is blurred in the case of insulin, which is composed of two polypeptide chains that are both derived from the same protein precursor.

Clinical Presentation Of Ghad

Sometimes, GHAD will first be suspected when there is severe neonatal hypoglycemia or other signs of hypopituitarism (hypothyroidism, small phallus in male babies, or neonatal hepatitis). During early childhood, children with GHAD are detected when they demonstrate short stature and subnormal rates of growth. Often these children will have proportionally small limbs, increased body fat, and a cherubic appearance.

Molecular Mechanisms And Defects Hypothalamus

Growth hormone (GH) synthesis and release are primarily regulated by two hypothalamic peptides somatostatin, which inhibits GH secretion, and growth hormone-releasing hormone (GHRH), which stimulates its release (Fig. 1). A third endogenous hypothalamic GH stimulating factor has been hypothesized and called growth hormone secretagogue (GHS, also known as growth hormone releasing peptide). GHSs have been synthesized, and are small molecules that promote somatotroph growth hormone release independently of, but synergistically with, GHRH (6,7).

Pituitary and Placenta

Simplified, schematic representation of the growth hormone axis. Growth hormone (GH) synthesis and release from somatotrophs is predominantly regulated by two hypotha-lamic hormones, growth hormone releasing hormone (GHRH) and somatostatin (SRIF). GHRH stimulates GH transcription, synthesis, and release via a Gs-protein coupled receptor (GHRH-R). SRIF antagonizes this effect via a Gi-protein coupled receptor (SRIF-R). GHRH activation of the heterotrimeric Gs-protein results in increased cAMP accumulation and activation of protein kinase A (PKA). PKA in turn phosphorylates and activates the cAMP response element binding protein (CREB) that binds to cAMP response elements in the promotor region of the Pit-1 gene to enhance transcription. Pit-1 augments GH-1 gene transcription leading to increased growth hormone synthesis. GH, acting via its receptor (GH-R), increases the synthesis and release of insulin-like growth factor 1 (IGF-1), which mediates somatotrophic effects...

End Organ Targets and Receptors

Unlike GH, the IGFs appear to play a major role in prenatal growth. Reece et al. and Verhaeghe et al. found a direct correlation between neonatal weight and cord serum IGF-1 levels (109,110). In 1996, Roth et al. confirmed that cord IGF-1 levels correlate with fetal size even in the macrosomia associated with diabetic pregnancies (111). It has been proposed that fetal IGF release is in part stimulated by growth hormone-like factors produced by the placenta in response to placental GHRH (111,112). Growth Hormone Receptor Defects Other identified GHR defects do not affect the extracellular domain region, and therefore manifest with normal or even elevated GHBP levels. Screening of children with idiopathic short stature for GHR defects is now underway (131). It has been hypothesized that GHR defects may prove to be a relatively common GHAD, accounting for up to 5 of all cases of idiopathic short stature (132). Patients with GHI from GHR defects often do not respond well to exogenous GH...

Diagnosis Of Gh Deficiency Classical Evaluation

Current practice incorporates a combination of clinical, auxologic, and laboratory criteria to define GHD. This begins with an evaluation of stature, relative to genetic expectations, and growth velocity, calculated from serial height determinations. Children who demonstrate consistently subnormal growth velocities for age are candidates for further screening. This generally begins with exclusion of non-GHAD causes of poor growth and incorporates a thorough history, physical examination, bone age assessment, and laboratory screening as appropriate. The majority of children referred to endocrine clinics for short stature will not have GHD. It is important to separate those children with normal variants of growth, such as constitutional delay of growth or puberty, or intrinsic short stature from those with chronic diseases that may be clinically silent except for their effects on growth.

Pulsatile Gh Secretion And Regulatory Mechanisms Affecting Ghrh And Somatostatin Secretion

Pulsatile GH secretion is under the control of two hypothalamic peptides, growth hormone-releasing hormone (GHRH) and somatostatin (somatotropin release-inhibiting factor SRIF). Our current understanding comes from a series of classical experiments which demonstrated that SRIF modulates GH trough levels and is important in the inhibition of GH secretion, whereas GHRH regulates pulsatile GH release from the anterior pituitary gland (6).

Nutritional Dwarfing Anorexia Nervosa

Nutritional dwarfing, an entity characterized by nutritional deprivation, body weight below 90 of ideal, growth retardation and growth failure, is associated with increased serum GH and decreased IGF-1 concentrations. The dissociation between GH and IGF-1 suggests that impaired somatic growth is related to reduced IGF-1 synthesis or action, whereas GH may mediate the metabolic adaptation to starvation through its effects on hepatic glucose production, lipolysis, and nitrogen conservation (22). In a recent study of 16 children with nutritional dwarfing, pubertal subjects had reduced mean 12-h GH concentrations in subjects (28). Spontaneous overnight GH secretion appears to be more sensitive to the effects of chronic undernutrition, and the pubertal subject is at particular risk for impaired GH secretion and potential compromise of final adult height. Despite these clinical findings, GH concentrations in a variety of malnourished states appears variable (28).

Concluding Remarks

Thoreau, E., Petridou, B., Kelly, P. A., Djiane, J., and Mornon, J. P. (1991). Structural symmetry of the extracellular domain of the cytokine growth hormone prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis. FEBS Lett. 282, 26-31. 17. de Vos, A. M., Ultsch, M., and Kossiakoff, A. A. (1992). Human growth hormone and extracellular domain of its receptor crystal structure of the complex. Science 255, 306-312.

Clinical Characteristics of Homozygous Individuals

GH replacement therapy has been successfully used for the treatment of short stature of many children with GHRHR mutations. They respond very well to the therapy, showing a brisk increase in longitudinal growth and they reach their target adult height if treatment is started in timely fashion.78,129,131,135 In some instances where IGHD diagnosis was made late, GH has been associated with gonadotropin-releasing hormone (GnRH) analog therapy in order to delay the onset of puberty and allow more time for the beneficial consequences of exogenous GH on longitudinal growth.142,143 However, the two largest kindreds (Sindh and Itabaianinha) have many adult IGHD subjects who have not been treated with GH, allowing an analysis of lifetime lack of GH due to such mutations. Affected subjects exhibit similar phenotypic features with proportionate short stature, poorly developed muscle mass, and excessive abdominal fat accumulation. Small developmental defects have been noted in some patients,...

Clinical Characteristics of Heterozygous Carriers

Studies have focused on individuals carrying heterozygous GHRHR mutations, in order to determine a possible gene dosage effect. The initial hypothesis proposed by Baumann et al.118,119 was that heterozygous carriers could present an intermediate phenotype. This hypothesis was based on early observations in the Sindh kindred, where heterozygous subjects showed lower than normal serum IGF-1 and IGFBP3 values, without short stature. The authors suggested a growth delay and, ''perhaps, adult height deficit in heterozygous state,'' while their data were consistent with a partially impaired GH-IGF-1 axis.119 When we examined a rather large number of subjects heterozygous for the Itabaianinha mutation, we found that adult height and serum IGF-1 levels were not significantly decreased compared to subjects homozygous for the normal allele. However, subtle effects were seen on body composition and body weight.167 Heterozygous subjects had a lower weight, with reduced body mass index and body...

Conclusions and Future Directions

There is a constant desire for systems to evolve and meet the ever-changing needs of researchers. This evolution has persisted in the field of inducible mammalian expression systems. One important use of inducible expression systems has been to generate transgenic mice that have regulated expression and, more specifically, targeted regulated expression. A unique system has been described by Wang et al. (1997) that allows for both inducible and targeted expression in transgenic mice. This system is outlined briefly in Fig. 5. It is a two vector system. The first vector is a regulatory vector that expresses a transactivator from a tissue-specific targeted promoter (liver-specific TTR promoter). The transactivator is a mutated human progesterone receptor ligand-binding domain fused with a hybrid of the Gal4 DNA-binding domain and the VP 16 transacti-vation domain. The vector also encodes insulator sequences that were added to help block suppressive effects of the surrounding chromosome...

The Shox Gene Deletions

SHOX mutations have been found in three disorders idiopathic short stature (SS MIM 604271), Leri-Weill dyschondrosteosis (LWD MIM127300), and Langer mesomelic dysplasia (MIM 249700) (55). In addition, SHOX haploinsufficiency is responsible for the skeletal anomaly in Turner syndrome patients. Approximately 2-7 of individuals with idiopathic SS and 60-100 of LWD patients have SHOX mutations (56-59). The rare and more severe Langer mesomelic dysplasia has homozygous or compound heterozygous mutations of the SHOX gene (56). A striking feature of SHOX mutations is that there is considerable phenotypic heterogeneity among the patients, and no correlation exists between the type and position of a mutation within the gene and the resulting phenotype. Complete gene deletion or the same point mutations could result in SS or LWD, and there is a significant inter- and intrafamilial variation in the severity of the phenotype, indicating the involvement of modifiers (58).

Analysis and Manipulation of Recombinant Glycoproteins Manufactured in Mammalian Cell Culture

Since microbial cells are easier to manipulate and have lower production costs than mammalian cells, they are the method of choice for peptides and simple proteins such as insulin and growth hormone. However, many therapeutic proteins require complex post-translational modifications such as glycosylation, gamma-carboxylation, and site-specific proteolysis, and mammalian cells are uniquely equipped to perform these operations.

Contiguous Gene Syndromes at Xp21

Contiguous gene syndromes at two regions of the X chromosome. The maps show the distances (in megabases) of the genes from Xp telomere, taken from the NCBI map viewer. Not all genes in the areas are shown. Lines at the left side of the maps depict regions deleted in the patients. A line in most cases represents deletions in a collection of patients who have the same phenotype but different deletion breakpoints. The dashed ends of the line cover the regions where the breakpoints may be located since most breakpoints of the deletions have not been well mapped. PAR1, pseudoautosomal region 1 SS, short stature LWD, Leri-Weill dyschondrosteosis CDPX, X-linked chondrodysplasia punctata MR, mental retardation XLI, X-linked ichthyosis, KAL1, X-linked Kallmann syndrome OA1, Ocular albinism type 1 MLS, microphthalmia with linear skin defects AHC, adrenal hypoplasia congenital GKD, glycerol kinase deficiency DMD, Duchenne muscular dystrophy BMD, Becker muscular dystrophy CGD, chronic...

Endocrinology of Growth

Postnatal growth can be considered to consist of at least three distinct phases infancy, childhood, and puberty. The infancy component is largely a continuation of the longitudinal growth process observed in utero. This displays a peak growth velocity around 27-28 weeks of gestation with a decline in growth rate during the last trimester of pregnancy. Birth, in a sense, is incidental to this declining growth rate, which continues during the first 3 years of life, reaching a plateau at or around the fourth year of life and remaining at this level until the commencement of the pubertal growth spurt. This plateau is interrupted in a large number of children by a juvenile or mid-growth spurt of small magnitude, which occurs between 6 and 8 years of age. The factors influencing these distinct growth periods are different. We know little of the factors influencing fetal and early infant growth but know from animal experiments that nutrition plays a key role. With the appearance of the...

Pregnancy and lactation

Marked changes occur in the breast during pregnancy under the influence of a variety of hormones (e.g. oestrogens, progestogens, prolactin, insulin, growth hormone and chori-onic gonadotrophins). There is an increase in the number and size of lobules, and an increase in the number of acini within each lobule. During the third trimester, secretory vacuoles of lipid material appear in the epithelial cells, and is the precursor of milk production. Following birth, milk is secreted by the epithelial cells into the ductules, mainly under the influence of

Ethical Issues Regarding Treatment Of Shortstatured Children

There is agreement about the treatment of the short-statured GH deficient child. What is controversial is the use of recombinant hGH in the treatment of the non-GH deficient child. This discussion is separate from the problems inherent in diagnosing GH deficiency as previously reviewed in this chapter. In the United States, Food and Drug Administration-(FDA) approved indications for hGH treatment at the time of preparation of this chapter include GH deficiency, growth failure associated with chronic renal failure and Turner Syndrome, wasting in AIDS and GH-deficient adults. The treatment practices in non-GH-deficient, short-statured children by U.S. pediatric endocrinologists were recently reported in the Journal of the American Medical Association (130). Because of the controversial nature of this common practice among pediatric endocrinologists, this article was accompanied by an editorial (131). An arbitrary definition of non-GH-deficient children with short stature would include...

Interleukin4 and IRS2 Signaling

In addition to IL4, other cytokines promote IRS1 or IRS2 tyrosine phosphorylation, including IL-7, IL-9, and IL-13 growth hormone prolactin and leukemia inhibitory factor (LIF) and interferon 14 . In particular, comparisons between IL-4 and IL-9 reveal unique signaling 67 . IL-4 and IL-9 receptors share the common IL-2Ry chain, so the signaling mechanism that establishes cytokine specificity and redundancy are not well understood. However, unlike IL-9, IL-4 receptors utilize IRS-protein in unique ways. IL9-Ra does not contain an NPXY motif to engage the PTB domain of IRS1 or IRS2, so it couples through the pleckstrin homology. Unlike IL-4 signaling, IL-9 does not promote SHP2 binding

The Prader Willi Syndrome

The minor diagnostic criteria include poor fetal movements, infantile lethargy, weak cry, and compulsive behavior with tantrums and outbursts. Also of note are sleep disturbances or apnea, short stature, hypopigmentation, small or narrow hands and feet, ocular anomalies, thick but scant saliva, speech articulation defects, and a tendency to skin ''picking.'' Other findings that often support the diagnosis include a high pain threshold, decreased vomiting, body temperature instability, kypho-scoliosis, osteoporosis, early adrenarche, unusual visual-spatial skills as seen from the ability to complete jigsaw puzzles, and normal neuromuscular abilities.

Thalassemia due to mutations in transacting factors

The second example of a trans acting mutation causing b thalassemia has been identified in patients with a rare, autosomal recessive syndrome called trichothiodystrophy characterized by dry photosensitive skin, brittle hair, short stature and variable degrees of mental retardation. Many of these individuals inherit mutations in one protein (the XPD helicase) of the multicomponent, general transcription factor TFIIH (Viprakasit et al., 2001).

Clinical Manifestations

Hand-Schuller-Christian disease (multifocal LCH) has similar bone granulomas along with other systemic manifestations. The skeletal anatomy of the head and neck is prominently involved. Mandibular defects include severe gingivitis, loss of mandibular height, and multiple loose teeth. The skull can have a geographic skull appearance on plain films secondary to multiple lesions. Involvement of orbital bones can result in changes in vision, and blindness can occur. Sellar involvement around the pituitary can lead to hypopituitarism, resulting in short stature and diabetes insipidus (2).

The Potential Maternal UPD2 Syndrome

The clinical characteristics of maternal UPD2 (Table 6), as defined from four cases, are listed in (Harrison et al., 1995 Hansen et al., 1997 Shaffer et al., 1997 Webb et al., 1996). They include (i) a gestational length shortened by oligohydramnios and frequent Cesarian section (ii) severe IUGR, not related to gestational age (iii) severe neonatal and postnatal pulmonary problems, requiring oxygen therapy up to the age of 1 year in one case (iv) hypospadias in two of the three male cases and occasional malformations such as preauricular pits (Shaffer et al., 1997), patent ductus arteriosus, and pyloric stenosis (Webb et al., 1996) (v) persistent growth retardation with short stature, small head, and poor weight gain documented up to 8 years of age (Table 6) (vi) normal developmental patterns (vii) an advanced maternal age of 32.2 years. Figure 5 demonstrates the relatively favorable outcome of the first case reported (Harrison et al., 1995).

Validity of Accelerated Aging Phenotypes

It should be noted that the mutations that lead to increased longevity in nematodes, flies or mice are likely to do so only at the cost of some selective disadvantage, often not obvious under laboratory conditions (Jenkins et al., 2004). For some of the mouse longevity mutants, such as the growth hormone deficient Ames dwarf mice, fitness costs are readily apparent in the form of infertility and hypothyroidism (Bartke and Brown-Borg, 2004). However, for another longevity mutant in the mouse, p66SHC, there is no obvious selective disadvantage

M45 Is a Cell Type Specific Survival Factor

Betaherpesviruses, including HCMV, encode the UL45 genes that are related by sequence but not function to ribonucleotide reductase (Chee et al. 1990 Patrone et al. 2003 Lembo et al. 2004). Viral mutants that disrupt the MCMV M45 gene induce apoptosis and are growth-restricted in endothelial cells and macrophages but not fibroblasts, bone marrow stromal cells, or hepatocytes (Brune et al. 2001). Although early and late genes are expressed, infection induces apoptosis and infectious progeny are not produced. Assays predictive of apoptosis, including nuclease activity and phosphatidylserine exposure, implicate this pathway however, a direct link between decreased apoptosis and rescued growth has not been established. Further, M45-dependent survival in apoptosis models or viral replication has not been demonstrated, and it is unclear how the phenotype of the mutant virus relates to apoptosis pathways and M45. However, disruption of M45 produces a nonpathogenic virus (Lembo et al. 2004),...

Ambulatory Monitoring Devices

Advances in technology have led to the expansion in the use of wireless ambulatory monitoring devices that are now capable of measuring ever greater numbers of biomark-ers, including skin conductance, skin temperature, respiration rate, pulse rate, sleep wake cycle, to name but a few. These devices have the advantages of being small, lightweight, and easy-to-wear, often in the form of a wristband (e.g., The SOMNOwatch, SOMNOmedics, DE) (for a review see Pantelopoulos and Bourbakis,

Clinical Description Of The

The condition was first described some 40 years ago (Prader et al., 1956). The clinical phenotype of PWS is characterized by neonatal hypotonia and developmental delay, followed by hyperphagia and major obesity, short stature, secondary hypogonadism, mild dysmorphism, small hands and feet, and mild to moderate mental retardation with learning disability. Consensus diagnostic criteria have been established and proven to be satisfactory for the clinicians (Holm et al., 1993). The frequency of the syndrome is on the order of 1 in 10,000 to 1 in 15,000 (Cassidy, 1984). There is wide variability in severity and a discrepancy between the clinical presentation in infancy and that in childhood or adulthood (Mascari et al., 1992). Initially, in the neonatal period hypotonia, impaired sucking reflex and failure to thrive attract parental and clinical attention feeding difficulties are thus a major problem. This sharply contrasts with the second phase of the syndrome, usually between ages 2 and...

Albright hereditary osteodystrophy

Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to germline mutations in GNAS1 that decrease expression or function of the heterotrimeric GTP binding protein, G alpha s. Maternal transmission of GNAS1 mutations leads to AHO (characterized by short stature, obesity, skeletal defects, and impaired olfaction) plus resistance to several hormones (e.g. parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyr-oidism). Studies in both mice and humans demonstrate that GNAS1 is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues, thus multihormone resistance occurs only when Gs (alpha) mutations are inherited maternally (Weinstein et al., 2002).

Leptin receptor deficiency

A mutation in the leptin receptor has been reported in several obese subjects from a consanguineous family of Kabilian origin (Clement et al., 1998). Affected individuals were homozygous for a mutation that truncates the receptor before the transmembrane domain and the mutated receptor circulates bound to leptin. Although this mutation does not result in a complete null phenotype, there are a number of phenotypic similarities with the leptin-deficient subjects. Leptin receptor deficient subjects were also born of normal birth weight, exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behaviour when denied food. In contrast, some neuroendocrine features were unique to leptin receptor deficiency (Clement et al., 1998). The presence of mild growth retardation in early childhood with impaired basal and stimulated growth hormone secretion and decreased IGF-1 and IGF-BP3 levels and evidence of hypothalamic hypothyr-oidism in these subjects,...

Neuroendocrine Systems

Most neuroendocrine axes are regulated by the hypothalamic-pituitary unit, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-gonadal axis, the hypothalamic-pituitary-prolactin system, and the hypothalamic-pituitary-growth hormone axis. The sympatho-adrenal-medullary system with its hormones epinephrine and nore-pinephrine (see Section 5) and pancreatic insulin secretion (see Section 6) are further major neuroendocrine systems, while some tissues such as adipose tissues and the digestive tract also possess neuroendocrine properties (Druce et al, 2004 Kershaw and Flier, 2004). Corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone stimulate the release of a further set of glandotropic hormones ( hormones regulating a remote endocrine target gland) into the general circulation. Their binding to specific endocrine cells in the anterior pituitary induces the...

Reproductive biology

In comparison to other catarrhine primates, where males may be more than twice the size of females, humans have only a small degree of sexual dimorphism. Depending upon the population, humans have 4-7 statural dimorphism. Statural dimorphism differences are higher in populations with tall stature, and lower in populations with small stature. Human body weight dimorphism averages about 11 . Much human sexual dimorphism involves soft-tissue characters. Subcutaneous fat patterning, seen especially in breast, thigh, and buttock fat depots, is markedly different in human males and females. Females also carry a larger percentage of subcutaneous fat than males do. Even in hunter-gather groups, where humans are very active and lean, subcutaneous body fat as measured by skinfold thickness is 5-15 in males and 20-25 in females.

Endocrine Aberrations

During recent years of investigation abdominal visceral distribution of adipose tissue has been found to be associated with endocrine disturbances, confirming the original observation by Vague (6). These disturbances include an increased cortisol activity and a blunted secretion of growth hormone (GH) and sex steroids in both men and women (29-34). These endocrine perturbations can theoretically be a consequence of the obese condition but it has also been suggested that the endocrine aberrations can have causal effects (33,35).

Gammacarboxyglutamic Acid Gla Proteins

Gla proteins, including matrix Gla protein (MGP) and osteocalcin (OC), are vitamin K-dependent bone proteins that play a key role as mediators and inhibitors of osteoid formation (Price et al., 1982 Pauli et al., 1987). MGP is a secretory protein that is widely expressed in tissues including bone and vasculature (Price et al., 1982). Chronic Warfarin therapy leads to depletion of these vitamin K-dependent Gla proteins, resulting in an excessive mineralization disorder and closure of the growth plate with cessation of longitudinal growth (Price et al., 1982). These features are similar to those observed in the warfarin embryopathy due to exposure of the human fetus to warfarin anticoagulation in early pregnancy (Pauli et al., 1987). Knockout mice lacking MGP develop to term but die within two months due to arterial calcification and blood-vessel rupture (Luo et al., 1997). Additionally, these MGP-deficient mice exhibit inappropriate calcification of the growth plate leading to short...

Association Between GH Release and Sleep in Normal Adults

The fact that the secretion of growth hormone (GH) is markedly stimulated during sleep has been recognized for more than three decades. Early studies using the first available radioimmunoassays for GH demonstrated that the peripheral levels of this hormone increased rapidly following sleep onset (1-5). In normal adult subjects, the 24-h profile of plasma GH levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible pulse occurs shortly after sleep onset (3,4). This relationship between sleep onset and GH secretion appears to be most consistent in the human species, because it is more difficult to evidence in other mammals, although elevated blood GH levels have been observed during sleep in baboons, rhesus monkeys, dogs, lambs, and both immature and adult rats (6-12). Species differences could be From Human Growth Hormone Research and Clinical Practice Edited by R. G. Smith and M. O. Thorner Humana Press Inc., Totowa, NJ

Inhibitory Effects Associated with Awakenings

In a study where GH secretion was stimulated by the injection of growth hormone releasing hormone (GHRH) at the beginning of the sleep period, it was found that whenever sleep was interrupted by a spontaneous awakening, the ongoing GH secretion was abruptly suppressed (41). This inhibitory effect of awakenings on the GH response to GHRH was further demonstrated in a detailed study where sleeping subjects who had received a GHRH injection were awakened 30 min after the injection and then allowed to re-initiate sleep 30 min later (42). The subjects who were able to resume sleep rapidly showed a secondary smaller GH pulse. A near complete inhibition of the GH response to GHRH was also observed when the injection was given 20 min after a forced awakening around the end of the first third of nocturnal sleep (42). It has been suggested that this inhibitory effect of nocturnal awakenings on the GH secretory response to GHRH could be mediated by an increase in somatostatin release (42). This...

Development and the Life Course

Behavioral medicine broadens traditional organ-ismic disease models to include wider social, cultural, and developmental contributions to health and disease. Just as cognitive and emotional development is embedded in, and dependent upon, an immediate social context (Vygotsky, 1930), so the normal maturational stages of cognitive development (Piaget, 1971) occur within the context of a developing brain. Neuroimaging methods have been applied to investigate both the development of cognitive capacities (functional development) and physical alterations in brain structure during the life course (structural development). For example, Dubois and colleagues (2008) explored the influence of inter-uterine environment on the functional and anatomical development of brain in premature newborns, observing abnormal and delayed gyrification within growth restricted, but not other infants, including twins. Figure 51.3a illustrates the minimal gyral and sulcal development in the normal premature...

Transgenic Mice General Overview

Croinjection and subsequent stable integration of a metallothionine (MT)-growth hormone fusion gene resulted in a giant mouse phe-notype. With the ensuing reiteration of this approach by several investigators (Palmiter and Brinster, 1986), the mouse soon became the preferred animal for transgenic studies. Advances in mouse genetics and embryology allow for the routine manipulation of both the mouse and its genome (Bieberich et al, 1993 Polites and Pinkert, 1993). In fact, facilities for generating transgenic mice are now available around the globe, and the scientific community via the Internet is compiling several important databases for use. A list of these databases can be found at the following address The existence of these Internet resources is a strong indication of the widespread use and applicability of transgenic mice.

Transgene Overexpression A Means for Dissecting the Interplay between Genes in a Complex Hierarchical Pathway

Code the following proteins growth hormone (GH), produced in the somatotropes of the pituitary two hypothalamic releasing hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) insulin-like growth factor (IGFI and IGFII) synthesized in hepatocytes, and insulin-like growth factor-binding proteins (IGF-BP), also synthesized in the liver. In this axis GH regulates somatic growth indirectly by controlling the synthesis of IGF. Levels of GH are controlled positively by GHRH and negatively by somatostatin. Serum GH can also exert its own negative feedback. Finally IGF-BP neutralizes the activity of IGF, providing yet another level of control to this axis.

Treatment of GH Deficiency

More than 10 years ago, Thorner et al. demonstrated that repeated administration of GHRH via pulsatile infusion pump (1-3 g kg pulse sc for 6 mo) increased the growth velocity of two growth hormone deficient children (Fig. 5) (27). During GHRH treatment, the growth velocity of these patients increased to rates similar to those observed during therapy with conventional doses of growth hormone. Shortly thereafter, we showed a similar effect in a group of GH-deficient children treated over two weeks with pulsatile GHRH (1 g kg pulse q 3 h iv) or placebo (28). These studies also demonstrated that prolonged treatment with pulses of GHRH continued to stimulate pulses of GH secretion (Fig. 6) and increased the circulating concentration of IGF-1. Others have subsequently confirmed these results (29,30).

Adjuvant Enhancement of GHRH Therapy

Growth hormone (GH) responses to the pulsatile administration of GHRH(1-44)NH2, 1 g Kg iv at 3-h intervals, to two children with idiopathic GH deficiency. The times of the injections are shown by the arrows. The magnitude of the GH responses to the injections varies over time, and in the subject shown in the lower panel the average response increases as treatment continues. GH levels return to low values immediately after the injections are discontinued. Modified from ref. 28. Fig. 6. Growth hormone (GH) responses to the pulsatile administration of GHRH(1-44)NH2, 1 g Kg iv at 3-h intervals, to two children with idiopathic GH deficiency. The times of the injections are shown by the arrows. The magnitude of the GH responses to the injections varies over time, and in the subject shown in the lower panel the average response increases as treatment continues. GH levels return to low values immediately after the injections are discontinued. Modified from ref. 28.

The Search For

(i) Two distinct disorders are present in the same individual. The first molecu-larly proven cases of UPD7 were of this type (Chapters 1 and 4) (Spence et al., 1988), e.g., the individuals had both cystic fibrosis through homozygosity for a CF mutation due to maternal UPD7, as well as very short stature (due to the absence of the paternal copy of imprinted genes).

Pharmacology Mechanism of Action

Physiologic secretion of GH is normally pulsatile, with the majority of secretion during the first few hours of sleep (13). Maintenance of this pattern is dependent upon the balance between stimulation by GHRH and inhibition by somatostatin, both secreted by the hypothalamus. However, the factor or factors responsible for regulating secretion of these hormones are unknown. The mechanism of GH release by the growth hormone secretagogues is complex and not completely understood. Both animal and human data demonstrate that the secretagogues bind to pituitary somatotrophs and cause direct stimulation of GH secretion (3,12,14-23). The secretagogues also bind to cells within the hypothalamus (24) where the growth hormone secretagogue receptor has been identified (12). Most studies suggest that the physiologic action of the secretagogues occurs both at the pituitary and at the level of the hypothalamus, and therefore an intact hypothalamic-pituitary axis is required for a vigorous GH...

Vector construction and protein expression

To test whether vaccination with a DNA plasmid encoding a M. tuberculosis antigen could result in induction ofimmune responses, we constructed a vector containing the gene for antigen 85A (Ag85A). The vector backbone, termed V1Jns, contains the immediate early promoter and enhancer from cytomegalovirus (with intron A) and the transcription terminator from bovine growth hormone (Montgomery et al 1993, Shiver et al 1995), and had previously been shown to give high levels of expression for several different antigens and reporter proteins (not shown). The native mycobacterial signal sequence from Ag85A was replaced with the eukaryotic signal sequence from tissue-specific plasminogen activator protein, in order to facilitate expression and intracellular trafficking in eukaryotic cells. This

Long vs Short Acting Compounds GH Secretory Pattern and Hormonal Specificity

In clinical studies, single doses of growth hormone secretagogues, given intravenously, intranasally, or orally have resulted in a dramatic elevation in serum GH levels (to approx 40-70 ng mL) (38-45) accompanied by modest post-dose increases in serum cortisol (mediated by ACTH) and prolactin (46,47). Since growth hormone and prolactin secreting cells are derived from the same embryonic lineage, stimulation of prolactin can

Review Activities

C. growth hormone. c. growth hormone. a. growth hormone Describe how thyroxine affects cell respiration. Why does a person who is hypothyroid have a tendency to gain weight and less tolerance for cold Compare and contrast the metabolic effects of thyroxine and growth hormone. 10. Describe the conditions of gigantism, acromegaly, Laron dwarfism, and kwashiorkor, and explain how these conditions relate to blood levels of growth hormone and IGF-1.

Growth Factor Signaling

Production of IGF occurs both systemically and locally. Growth hormone regulates the levels of IGF generated by the liver, the major site of IGF production. Increased serum levels of IGF are critical for the proper maintenance of terminal end bud structures in the mammary gland. The role of IGF in prevention of or susceptibility to breast cancer stems largely from correlative evidence in human studies and direct evidence in rodent studies. Epidemiological studies analyzing possible roles for IGF in breast cancer have indicated that premenopausal women with serum IGF levels in the highest quartile have an increased incidence of breast cancer. Conversely, well established protective therapies such as tamoxifen, fenretinide, and caloric restriction are associated with a decrease in IGF serum levels. However, the most convincing evidence that high IGF levels and signaling may be related to breast cancer is obtained from genetically defined rodent models with alterations in the IGF...

Werner Syndrome as a Model of Human Aging

Werner syndrome (WS) is an uncommon, autosomal recessive human disease that displays clinical features suggestive of premature aging. The initial description of WS was by Otto Werner, a German medical student, in 1904 (Werner, 1985). Werner saw a family in the north of Germany consisting of four siblings, ages 31 to 40, who shared common features including short stature, premature graying of the hair, bilateral cataracts, skin changes (hyperkeratosis, scleroderma-like changes and ulceration) that were most severe on the feet and ankles, atrophy of the extremities, and, in females, an early short stature probable short stature, bilateral cataracts and scleroderma-like skin changes, any two other clinical, history or laboratory findings (1966) in their analyses of WS patients and pedigrees. Among the most consistent and earliest of the features of WS to be observed are short stature, bilateral cataracts, the early graying and loss of hair, and scleroderma-like skin changes. All four...

Graying And Loss Of Hair

Early graying and loss of hair are, together with short stature, among the earliest and most consistent changes observed in WS patients. Hair graying and loss start late in the second decade of life, and first affect the scalp and eyebrows. The loss of hair pigmentation is progressive and may lead over the course of a decade or more to complete loss of pigmentation. The premature graying and loss of hair also extend to other areas of the body, although these changes usually start later and may not be as extensive as the changes observed in the scalp and eyebrows.

ScaleUp of Intein Processes

Based on the stated assumptions, the overall product cost for the conventional process was calculated to be 38 g. However, incorporation of the scaled-up IMPACT step raised the cost to 87 g. Despite the fact that this is orders of magnitude cheaper than any conventional affinity-tag process, it is still economically unrealistic compared to most industrial large-scale protein-purification processes. For comparison, the total manufacturing costs estimated for Monsanto's bovine growth hormone are less than 5 g (Swartz 2001).

Genetic Basis Of Hormonal Carcinogenesis

Ysa Premium Reimbursement

And some of these are eventually relevant to the constellation of such mutations needed to produce the malignant phenotype. Ovarian steroid hormones drive the process of cell division directly and are, thus, the primary carcinogens. The amount of ovarian steroid hormones produced during each menstrual cycle is under strong genetic control, and the relevant genes are those in the relevant sex steroid biosynthesis and metabolism pathway (Table 1.1). We assume that there are common ( 1 ) sequence variations in these genes, which can produce meaningful differences in total ovarian steriod exposure over a woman's lifetime. Of course, the same, or novel, sequence variants in these genes can be associated with the progression of hormone-related cancers, as has been well documented for variants in the androgen receptor gene.20 The details of the endocrine pathways and the relevant candidate genes will be discussed by several of the chapters in this book, so further details are not provided...

Definition Of Nongenotoxic Carcinogens

Nongenotoxic carcinogens can affect the cell reproductive process by acting as cytotoxicants, inducing regenerative cell proliferation, and producing secondary critical effects such as inflammation (2). Cytotoxicity releases nucleases that may induce DNA damage. Cytolethality can induce regenerative cell proliferation, which can influence spontaneous tumor rates that result from pre-existing mutations. Inflammation can increase the generation of oxygen radicals that may induce mutations. Cell proliferation can also occur through more direct growth-stimulatory mechanisms. Chemicals that interact with hormone receptors (estrogens, androgens, growth hormone) or increase the synthesis of these hormones can increase cell division in responsive tissues and thus lead to increased growth of pre-existing tumor cells. Induced cell division may also result in conversion of DNA adducts (from endogenous or exogenous sources) to mutations before DNA repair can occur and affect expression of growth...

Potential Indications

A clear role for the growth hormone secretagogues has yet to be demonstrated. The secretagogues have both potential advantages and disadvantages compared to recombinant human GH. GH replacement therapy requires parenteral administration and results in a nonphysiologic serum GH profile with often supraphysiologic levels. Particularly in older individuals, these characteristics may contribute to the poor clinical tolerability that has been reported in several clinical trials (49-52). In contrast, the longer acting secre-tagogues, or frequent dosing with the shorter acting compounds, may result in increased GH secretion in a physiologic pattern, resulting in improved tolerability. In addition, oral (or intranasal) dosing is possible. In other indications where a modest physiologic increase in GH and IGF-1 levels is desirable, secretagogues may have advantages compared to the use of GH. However, it is likely that with chronic dosing with a secretagogue, supraphysiologic levels of GH...

Ocular Use Of Steroids

Glucocorticoids have important effects on the nervous system, including behavior and intracranial pressure. Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobactor pylori. Glucocorticoids given chronically suppress the pituitary release of adrenocorticotropic hormone, growth hormone, thyroid-stimulating hormone, and leutinizing hormone.

EEG and the Effects of Hormone Treatment

The administration of hormone replacement therapy (HRT) offers the promise of normalization of function, but EEG ERP has been used to determine whether general brain state or cognitive function indeed improved with treatment. Schneider and colleagues (2005) examined the effects of growth hormone (GH) replacement deficiency on the sleep EEG, using polysomnography in growth hormone-deficient patients. Results showed that the values for the obtained sleep parameters were similar to those for Golgeli and colleagues (2004) examined the effects of growth hormone (GH) replacement therapy on cognitive function in women with Sheehan's syndrome. Sheehan's syndrome is also known as postpartum hypopituitarism, a pituitary hormone deficiency as a result of life-threatening blood loss during or after childbirth. At baseline, amplitude and latencies of auditory oddball ERPs of patients showed longer latencies than those of controls. After 6 months of hormone replacement therapy, patients showed...

B Ghrhr Polymorphisms

Polymorphisms in the GHRHR have been reported but no role in IGHD disease has been established.78,127 On the other hand, some polymorphisms (A57T and M422T) have been associated with an increased response to GHRH through an augmented cAMP production.138,139 Although the presence of constitutively active GHRHR mutations could in theory be considered crucial for the development of GH-secreting pituitary tumors, several studies reported no increased risks of developing acromegaly in patients affected by those polymorphisms when compared to the general population, and analysis of tissues from GH-secreting adenomas failed to confirm this hypothesis.139-141 Very recently, two haplotypes of the GHRHR have been reported to account for 1.8 of the variation in adult height after adjusting for sex, age and population affinity, making it the strongest genetic contributor to normal human variation in height so far identified.141a

Diseases of genomic imprinting

Neurobehavioral disorders with distinct clinical manifestations (Ferguson-Smith et al., 2004 Nicholls and Knepper, 200l). Patients with PWS present with hypotonia at birth, obesity, short stature, mental retardation, hypogonadism and a characteristic facial appearance. AS is characterized by microbrachycephaly, large mouth with tongue protrusion and prognathism mental retardation is severe with absence of speech. Both diseases are associated with deficiencies in the same region of human chromosome 15q11-q13 due to an unequal crossing over between low copy repeats. These deletions are of paternal origin in PWS

Implications of the vIL6gp130 Tetramer Structure for the Active Gcsfgcsfr Extracellular Signaling Complex

351 302 Engine Comparison

Binding in the growth hormone receptor complex. Proc. Natl. Acad. Sci. USA 93(1), 1-6. 3. de Vos, A. M., Ultsch, M., and Kossiakoff, A. A. (1992). Human growth hormone and extracellular domain of its receptor crystal structure of the complex. Science 255(5042), 306-312.

Pharmacological Toxicological Effects

Hyperforin (4.5 ) were shown to have dose-dependent enhanced 5-HT levels in all brain regions. Norepinephrine levels were increased in the dien-cephalon and brain stem, but not in the cortex, and higher levels of hypericum were needed. Dopamine levels were only increased in the diencephalon region with doses similar to those required for increased levels of norepinephrine (12). Cott demonstrated that hypericum extracts had affinity for adenosine, y-aminobutyric acid (GABA)-A, GABA-B, benzodiazapine, and monoamine oxidase (MAO) types A and B receptors (3). However, with the exception of GABA-A and GABA-B receptors, it is unlikely that the concentrations required to produce a physiological effect can be reached (3). Other studies have shown that hypericum extracts do not have high affinity for GABA-A and -B (5). Additionally, H. perforatum extracts downregulate P receptors and upregulate 5-HT2 receptors in the frontal cortex when given to rats (3,11). Hypericum extract standardized to...

Physiological Aging

Animal model are similar to those seen in people. Equally relevant are reproductive changes with age, which include testis and ovary changes as well as the onset of reproductive senescence such as age of menopause. Many age-related changes and pathologies can also be studied and compared to human aging. A few parameters of interest include, but are not limited to, fat deposits, hormonal levels such as those of growth hormone, insulin and insulin-like hormones, and dehydroepiandrosterone (DHEA), atherosclerotic lesions, osteoporosis, arthritic changes, changes in reaction times with age, changes in senses, and the presence of cerebrovascular -amyloid protein (Finch, 1990). There are also examples of comparative studies aimed at specific age-related pathologies, and readers should consult other chapters in this book.

Case 2

A 43-year-old woman was reported who was referred for evaluation because of minor facial anomalies, myopathy, sterility, short stature, hearing loss, downward slant of palpebral fissures, bilateral ptosis, severe micro retrognathia, high arched palate, and scoliosis (Chen et al., 1999). Cytogenetic analyses showed the presence of one i(1p) and one i(1q) without normal chromosome 1 homologues. Fluorescence in situ hybridization analysis showed hybridization to only two chromosomes, consistent with the G-banded interpretation of i(1p) and i(1q). Molecular investigations using markers for chromosome 1 showed inheritance of only one set of paternal alleles and absence of any maternal alleles in the patient. The authors concluded that the adverse phenotype of the patient may be due to

Policy Matters

Some individuals worry, for example, that ''artificially'' extending human lives would cheapen our existence, whereas others point out that the modern medical enterprise has already drastically increased lifespans with no ill effects on society. Other subjects that the site has explored include the paucity of older people included in clinical trials the wisdom of using human growth hormone to combat symptoms of aging despite data suggesting that the substance curtails lifespan and how we might improve our flu-combating measures. It has discussed nanotech-nology, hormone replacement therapy, guidelines for keeping bones strong, and chronic pain, as well as age-related voice changes and hearing loss. SAGE Crossroads ponders such topics in News and Views articles as well as through Webcasts in which experts debate and discuss such matters.

Conclusions

The GHRPs were discovered by Cyril Y. Bowers and his colleagues in the late 1970s. Through Dr. Bowers' dedicated efforts, their potency and in vivo properties were perfected culminating in clinical demonstrations of sustained growth hormone release. Efficacy as measured by growth improvements in GH-deficient children has been demonstrated and other possible uses are being studied. It is remarkable that these secreta- Even with small molecule peptidomimetic leads, potency, selectivity, and good oral bioavailability were only achieved through the efforts of many chemists, biologists, and drug metabolism specialists. Clinical studies have been undertaken to determine if MK-0677 and other GH secretagogues will make a contribution to medicine. Regardless of that outcome, the potency and selectivity of 35S -MK-0677 played an important role in the identification and cloning of the GHS receptor. The awaited next step in the GHRP story is the identification of the putative natural hormone....

Cases 3 and

These two cases are presented together, as they were documented from a cohort of 54 uniplex families with cartilage-hair hypoplasia (CHH) (Sulisalo et al., 1997), an autosomal recessive form of chondrodysplasia, unusually frequent in Finland, where the locus was mapped to 9p21-p13 (Sulisalo et al., 1993b, 1994a). The pleiotrophic features of CHH include disproportionate short stature, hypo-plastic (thin and sparse) hair, defective immunity, and, more rarely, Hirschsprung disease and defective erythrogenesis an increased risk of malignancy also exists (Sulisalo et al., 1997).

Abstract

Somatostatin (SRIF) is a 14 amino-acid-containing peptide primarily expressed in the hypothalamus. It is a major physiological regulator of growth hormone (GH) secretion and is critical in maintaining the pulsatile release of GH. SRIF induces its biological effects by interacting with membrane-associated receptors, of which a family of five have recently been cloned. The cloned receptor subtype referred to as sstr2 may have an important role in mediating the inhibitory effects of SRIF on GH secretion. This is suggested from pharmacological studies showing that a large series of SRIF analogs, including the clinically used peptides octreotide and lantreotide, had a similar rank order of affinities for binding to sstr2 and to inhibit GH secretion. Stimulation of sstr2 may lead to inhibition of Ca2+ influx into somatotrophs to reduce GH secretion. Structural analysis of the cloned sstr2 has revealed binding domains of the receptor that may be useful in the development of antagonists and...

Structure

Although the crystal-structure analysis of TPO has been completed, it has not been published. The areas of TPO that bind the TPO receptor are probably analogous to those of human growth hormone and EPO. Based on the similarity of these three cytokines, it has been proposed that Lys138 of helix D and Pro42 and Glu50 of loop AB may constitute one binding region, and Arg10 and Lys14 of helix A may constitute a second binding region that participates in the dimerization of TPO receptors (23). This suggestion has been partly confirmed by monoclonal antibody (MAb) studies. Two MAbs that block TPO binding to its receptor have determinants in helix D (24). These results again suggest that TPO has two receptor binding sites that help dimerize its receptor.

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