How to Grow Taller

Grow Taller 4 Idiots

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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).

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...

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).

Growth Hormone Gh And Somatomedins Igfs

Although this subject overlaps that of Chapter 5 on anterior pituitary hormones, it is a reasonable starting point since IGF-I is a major growth factor. The relationship between growth hormone and IGF-I is shown in Figure 19-1. Here it is shown that GH is released through the action of hypothalamic growth hormone-releasing hormone (GRH), as described earlier in Chapter 3. The GH released into circulation has two effects One effect is to directly act on lipid and fat metabolism, analogously to Cortisol action, in a manner to oppose the actions of insulin and IGF-I, as shown by its ability to directly increase blood sugar (Figure 19-1). The other action of GH is on liver and other organs to generate IGF-I, which, like insulin, produces skeletal growth as well as tissue growth. IGF-I is active as a negative feedback agent on the hypothalamus and causes the production of somatostatin (GIH), which inhibits the release of GH from the anterior pituitary, and it also acts at the level of the...

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

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.

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...

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).

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...

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).

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...

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).

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...

Biological And Molecular Actions

Hormones are now believed to regulate thymosin production. Growth hormone increases levels of thymosin i. TSH may also have an influence. The role of glucocorticoids on the thymus (Chapter 10) is well known and there may be specific interactions between glucocorticoids and thymosin production.

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 pg 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 pg 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.

Epidermal Growth Factor Egf Family

FIGURE 19-2 Structure of single-transmembrane-segment receptors that form homologous dimers the growth hormone receptor. One GH molecule binds to identical binding sites on the extracellular domains of two GH receptors that form a homodimer. The intracellular domains associate with a tyrosine kinase of the Janus family of kinases. An encircled P denotes a potential tyrosine phosphorylation site on the intrecellular portion of GH receptor. Reproduced with permission from Gammeltoft, S. and Kahn, C. R. (1995). Hormone signaling via membrane receptors. In Endocrinology (L. J. De-Groot, ed.), 3rd ed., Vol. 1, pp. 17-65. W.B. Saunders Co., Philadelphia, PA. FIGURE 19-2 Structure of single-transmembrane-segment receptors that form homologous dimers the growth hormone receptor. One GH molecule binds to identical binding sites on the extracellular domains of two GH receptors that form a homodimer. The intracellular domains associate with a tyrosine kinase of the Janus family of kinases. An...

Transforming Growth Factor Tgf3 Family

FIGURE 19-3 Close-up of interfaces between hormone and receptors (A) binding site I (B) binding site II. The hGH is represented by a space-filling model and the receptors by a stick model. The hGH backbone atoms are cyan, side chain carbons are white, and side chain oxygens and nitrogens are red and blue, respectively. The receptor carbon atoms are in yellow, with red oxygens and blue nitrogens. Selected residues are labeled. This figure is reproduced in black and white from a colored illustration with permission from de Vos, A. M., Ultsch, M., and Mossiakoff, A. (1992). Human growth hormone and extracellular domain of its receptor Crystal structure of the complex. Science 255, 306-212. FIGURE 19-3 Close-up of interfaces between hormone and receptors (A) binding site I (B) binding site II. The hGH is represented by a space-filling model and the receptors by a stick model. The hGH backbone atoms are cyan, side chain carbons are white, and side chain oxygens and nitrogens are red and...

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...

Ectopic Production Of Hormones By Tumor Cells

A case was reported of acromegaly from ectopic growth hormone-releasing hormone (GHRH) secreted to an extent 1000 times greater than normal by a bron- chial carcinoid tumor. In this case, plasma growth hormone levels were increased. There was metastatic disease demonstrated by the production of GHRH and GH by tumor tissue in the lung, submaxillary gland, and breast. The condition was treated with chemotherapy (nitrosourea, CCNU, and 5-fluorouracil in repeated cycles) and the tumors regressed. This is a rare syndrome and also unusual in its positive response to

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...

Tumor Suppressor Genes

Instead of being related in structure to membrane growth hormone receptors, certain oncogenes encode information for proteins involved in transducing signals from the membrane. An example of this is the ras family of oncogenes. Ras functions in every way like a normal GTP-binding protein in the signal transduction pathway of many membrane receptors, usually resulting in the activation of adenylate cyclase as typified by the adrenergic receptors. However, ras proteins in mammalian cells do not seem to interact with adenyl-

Clinically Relevant Endocrine Disorders1

Inappropriate and continued secretion of growth hormone by a tumor of pituitary cells which leads to soft tissue swelling and hypertrophy of the skeletal extremities (usually in the third or fourth decade). peripheral unresponsiveness to the hormone afflicted individuals frequently are of short stature, with mental retardation and short metacarpals and or metatarsals.

Actions of Melatonin on Anterior Pituitary

Regulation of Growth Hormone Release It has been suggested for some time that melatonin could inhibit the release of growth hormone from the anterior pituitary. Other work suggests that melatonin accomplishes this by stimulating the release of somato- statin, which has been observed by using expiants of rat medial basal hypothalamus. The action of somatostatin on inhibiting growth hormone release is described in Figure 5-23. Interestingly, melatonin concentrations effective in stimulating somatostatin release were in the range of 10-100 nM for expiants of hypothalamus.

Clinical Aspects

Hypocalcemia Female And Male Pdf

Pseudohypoparathyroidism is a rare genetic disorder involving bone and mineral metabolism. It is probably inherited as an X-linked dominant trait with variable penetrance and is characterized by signs and symptoms similar to those of hypoparathyroidism. However, in this disease state there is a peripheral resistance to the biological actions of parathyroid hormone and an elevated secretion of PTH. Characteristic clinical features include a round face, short stature, brachydactylia, especially of the metacarpal and metatarsal bones as a result of early epiphyseal closure (see Figure 9-15), and in some instances ectopic soft tissue calcifications.

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

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....

Chemistry

And the same or that both types of cells may exist. In the set of dual-controlling releasing hormones, there are growth hormone-releasing hormone (GRH) and growth hormone release-inhibiting hormone (GIH or GRH is a polypeptide. -Endorphin is active in causing the release of growth hormone and PRL and in inhibiting the release of gonadotropins and TSH. i-Endorphin arises from the proopiomelanocortin precursor in corticotrophic cells of the anterior pituitary. It is a cleavage product of 3-lipotropin, which is directly translated to proopiomelanocortin. It is possible that -endorphin could stimulate GH release indirectly by increasing the release of GRH or inhibiting the release of somatostatin. A peptide and its partial degradation products have been discovered by the R. Guillemin group in human pancreatic carcinoma. This 44-amino acid peptide possesses growth hormone-releasing activity and appears to be human GRH. Its structure is shown in Figure 3-8. Growth hormone-releasing hormone...

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...

Model Properties

Model simulation showing pulsatile release of growth hormone as a consequence of pulsatile application of GRF desensitization to repeated pulses of GRF a complete resensitization as a result of infusion of somatostatin in the absence of pulses of GRF almost complete inhibition of release as a result of somatostatin infusion even though the GRF pulses continue a partial resensitization as a result of this somatostatin infusion as pulses of GRF continue. Parameters used were kl 1, k2 0.002, k3 0.036, k4 1.5, k5 30, k6 5, k7 5, k8 0.5, r0 0.05, s0 0, S0 0.05. Fig. 2. Model simulation showing pulsatile release of growth hormone as a consequence of pulsatile application of GRF desensitization to repeated pulses of GRF a complete resensitization as a result of infusion of somatostatin in the absence of pulses of GRF almost complete inhibition of release as a result of somatostatin infusion even though the GRF pulses continue a partial resensitization as a result of this somatostatin...

Chondrocyte

Figure 9-8 summarizes the scope of the vitamin D endocrine system. The steroid hormone la,25(OH)2D3 is produced only in accord with strict physiological signals dictated by the calcium demand of the organism a bimodal mode of regulation has been suggested. On a time scale of minutes, changes in the ionic environment of the kidney mitochondria resulting from the accumulation and release of calcium and or inorganic phosphate may alter the enzymatic activity of the 1-hydroxylase. In addition, parathyroid hormone has been shown, on a time scale of hours, to be capable of stimulating the production of la,25(OH)2D3, possibly by stimulating the biosynthesis of the 1-hydroxylase. It is also relevant that la,25(OH)2D3 is a stimulant for the renal production of 24,25(OH)D3. Thus, under normal physiological circumstances, both renal dihydrox-ylated metabolites are secreted and are circulating in the plasma. There is evidence of a short feedback loop for both of these metabolites to modulate and...

Sex Steroids

No differences in mean 12-h GH concentrations was demonstrated between groups of normal-statured males and growth-retarded males with constitutional delay of growth (90). The constitutional growth delay males were significantly shorter, had a greater bone age delay and diminished growth velocity relative to their normal-statured peers. These constitutional growth delay males had a longer secretory burst half-life relative to their normal statured peers, a feature previously described in girls with Turner syndrome (91). Paradoxically, the constitutional growth delay males had a decreased mass of GH released per burst. The authors theorize a deficiency in the amount of GHRH released per GH secretory event further supported by previous work in prepubertal males with constitutional growth delay (92).

Development

A high level of tonic, i.e., non pulsatile, secretion (60). As the infant matures, GH pulse frequency and amplitude decrease and tonic secretion diminishes (60). A pulsatile pattern of GH release, with increased pulse amplitude during sleep, is present in prepubertal boys and girls (61). During puberty, the amplitude of the pulses but not the frequency is increased, particularly at night (62,63). Maximal overall GH concentrations are reached in early puberty in girls and in late puberty in boys (63). Because of the robust nature of the relationship between sleep and GH release in both prepubertal and pubertal children, it has been proposed that a sleep test, i.e., repeated measurements of plasma GH during overnight sleep, may provide a reliable index of GH secretion and a useful test of GH deficiency (64,65). A number of reports examining the relationship between nocturnal GH secretion and SW sleep in children have indicated that the temporal association observed in adult is already...

Genetic Basis Of Hormonal Carcinogenesis

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...

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). This contrasts with the interaction of D1.3 with E5.2 in which nearly all the contacting residues play a demonstrable role in binding ligand (> 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...

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

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).

Proposal 7 Discovery Of Iaa Or Ga3binding Proteins And Isolation Of Novel Genes In Plants

GA3 and IAA are two well-known growth hormones that have been well studied in view of their actions on the physiology and biochemistry of plants. In spite of the fact that some laboratories have recently been working on the molecular biology of these hormones, the mechanisms by which GA3 and IAA can promote the growth of plants, especially in mutant phenotypes, are not really understood well. It appears that not much progress has been made so far. However, these two chemicals are very important hormones for normal plant development. From this point of view, and in order to promote new studies on the models of actions of these two hormones, one may launch a new proposal to the Department of Energy (DOE) or the U.S. Department of Agriculture (USDA) for the identification and isolation of GA3- and IAA-targeting proteins and novel genes, based on the hypothesis that the mechanisms of these hormones depend on hormone-protein interactions. This is an excellent research project for a Ph.D....

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...

Inorganic Nitrogen in Soil

Soil inorganic nitrogen is commonly less than 2 of the total nitrogen of surface soils and undergoes rapid changes in composition and quantity. Inorganic nitrogen varies widely among soils, with climate, and with weather. In humid, temperate zones, soil inorganic nitrogen in surface soil is expected to be low in winter, to increase in spring and summer, and to decrease with fall rains, which move the soluble nitrogen into the depths of the soil (105). Despite being small in magnitude, the inorganic fraction is the source of nitrogen nutrition for plants. Unless supplied by fertilizers, inorganic nitrogen in soil is derived from the soil organic matter, which serves as a reserve of nitrogen for plant nutrition. Plant-available nitrogen is released from organic matter by mineralization and is transformed back into organic matter (microbial cells) by immobilization. Absorption by plants is the chief means of removal of inorganic nitrogen from soils, although nitrate leaching and...

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.

Clinical Applications for Skeletal Determinations

There are two main applications for evaluations of skeletal maturation the diagnosis of growth disorders and the prediction of final adult height. Secondary growth deficiency is related to factors, generally outside the skeletal system, that impair epiphyseal or osseous maturation. These factors maybe nutritional, metabolic, or unknown, as in the syndrome of idiopathic (constitutional) growth delay. In this form of growth retardation, skeletal age and height may be delayed to nearly the same degree, but, with treatment, the potential exists for reaching normal adult height. The adult height of a child who grows up under favorable environmental circumstances is, to a large extent, dependent on heredity. The final height of the child may, therefore, be postulated from parental heights. Indeed, various methods of final height predictions, which take into account parental height, have been described 6 . A child's adult height can also be predicted from his or her heights at earlier ages,...

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.

Improved Physical Performance And Preservation Of Muscle Mass

BC has been used by athletes mainly as a natural source of IGF-I because it has an anabolic effect and is involved in the regulatory feedback of growth hormone. It is taken in the belief that protein catabolism will be reduced during intense training periods and physical performance will improve.

Epidemiology Prion Diseases

Cases of prion diseases transmitted from one person to another and, more recently, from one species to another (i.e., transmissible or infectious form of CJD) have been documented. Person-to-person transmission has been termed iatrogenic CJD. Cases have been reported after receiving pituitary growth hormone therapy derived from human cadavers, dura mater grafts, corneal transplants, and after neurosurgery and epilepsy monitoring that used contaminated surgical instruments and depth electrodes (Brown et al., 2000). In the 267 cases of iatrogenic CJD that have been documented worldwide, the majority of cases have been caused by receiving cadaveric human growth hormone (139 cases, 52 ) and dura mater grafting (114 cases, 43 ). The median incubation periods for these types of iatrogenic CJD are between 6 and 12 years. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4 , and the proportion acquiring CJD from dura mater grafts range from 0.02 to 0.05 ....

Family A Gpcrs 521 Monoaminergic Receptors

The dopamine D2 receptor is expressed by pituitary lactotrophs and somatotrophs. Dopamine receptor agonists are potent inhibitors of prolactin (PRL) secretion and are effective in treating prolactinomas, tumors of pituitary lactotrophs that produce prolactin.16 First generation dopamine receptor agonists such as bromocriptine have been available since the mid-1970s and are used widely to treat pituitary tumors. Cabergoline, a new long-acting safe, high-affinity selective D2 agonist has been approved to suppress PRL secretion and reduce tumor size.17 Chimeric ligands that incorporate both intrinsic dopaminergic and somatostatiner-gic properties (see Section 5.2.1.3.1) by selectively binding to D2 and SSTR2 receptors have shown increased potency in suppressing PRL and growth hormone (GH) and are currently in the experimental phases of investigation for treatment of pituitary tumors.

Somatostatin Receptors

The five somatostatin receptors (SSTR1 through SSTR5) belonging to the family of neuroendocrine receptors are widely expressed in pituitary gland, spleen, and the gastrointestinal tract.27 Somatostatin exists as two biologically active forms (SS-14 and SS-28) and inhibits secretion of growth hormone (GH) from the pituitary gland. The pituitary gland is crucial for the maintenance of several homeostatic functions including growth, metabolism, and reproduction. Since pituitary tumors are associated with unrestrained secretion and action of trophic hormones, treatment is aimed at the suppression of hormone hypersecretion, inhibition, and prevention of pituitary tumor growth.16,28 Pituitary tumors account for 15 of intracranial tumors and are usually benign and nonmetastatic.

Functional Expression Of G Proteincoupled Receptors In Yeast

Certain classes of GPCRs, including secretin and growth hormone releasing hormone receptors, possess ligand binding determinants in a large N-terminal extracellular domain that can be used in the yeast two-hybrid system to examine GPCR ligand interactions. The interaction of the GHRH receptor N-terminal domain with GHRH was evaluated using this system by fusing the complete N-terminus of the human GHRH receptor to one half of the two-hybrid Gal4p protein, and fusing GHRH to the other half 90 . In the two-hybrid system, the expression of a reporter gene that allows growth on selective media occurs only when a protein-protein interaction is formed (see section below). The proteinprotein interaction formed between the GHRH receptor domain and GHRH was sufficient to promote growth of yeast cells on selective media, and this interaction was disrupted when specific mutations known to interfere with GHRH binding were introduced into GHRH 90 . This approach may be extended to other members of...

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

The Inheritance of Continuous Characteristics

Not all characteristics exhibit discontinuous pheno-types. Human height is an example of such a character people do not come in just a few distinct heights but, rather, display a continuum of heights. Indeed, there are so many possible phenotypes of human height that we must use a measurement to describe a person's height. Characteristics that exhibit a continuous distribution of phenotypes are termed continuous characteristics. Because such characteristics have many possible phenotypes and must be described in quantitative terms, continuous characteristics are also called quantitative characteristics.

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.

Terminology and Definitions

To underline the fact that many hormones decline with age, the word adre-nopause has also been used to describe the diminution of the adrenal androgens DHEA and DHEAS (see section titled hormones), and somatopause to describe the same in the somatotrophic hormone, growth hormone (GH).

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).

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

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...

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.

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

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...

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

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.

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...

Transmissible spongiform encephalopathies prion dementias

Human examples of these disorders include Creutzfeld-Jacob Disease (CJD) and kuru (formerly found in Papua New Guinea cannibals this epidemic peaked in the 1960s and is now more or less extinct, due to the decline of cannibalism). Sporadic CJD has always rarely occurred. Iatrogenic CJD cases involved transmission of the condition by use of pituitary tissue ('harvested' to obtain growth hormone) from brains post-mortem that turned out to be CJD infected. New variant (nvCJD) cases are those linked to BSE. Although at the height of the health scare regarding BSE, huge numbers of cases were predicted, as of August 2006, only 156 had been identified (http www.cjd.ed.ac.uk figures.htm). In some families, these dementias appear to be due to an inherited prion gene mutation, which follows an autosomal dominant pattern. Other cases are infective, due to an abnormal prion protein acquired in various ways. The disorders can be transmitted to experimental animals, and human cases have followed...

Transcriptionbased Screening With Reporter Genes

Inducible promoters and response elements are critical tools for the use of reporter gene technology, as they provide the ultimate on-switch that activates transcription of the reporter gene. Promoter activity is controlled or modulated by regulatory regions of the DNA that are usually, but not always, found in the 5' end of the gene. These regulatory regions encode the response elements that act as sensors of activation of a cell signal pathway. Ideally, for screening purposes, the promoter should be strong but controlled by the desired response element in a way that maintains baseline transcription at low levels in the absence of the cell activation. The cytomegalovirus promoter is a strong promoter, but constitutive expression of the reporter gene often leads to high background. The herpes virus thymidine kinase, SV40, and growth hormone promoters have been used in many constructs.

Octreotide Sandostatin

Dose (ped) 1-10 mcg kg every 12 hrs beginning at low end of range and increasing by 0.3 mcg kg dose at every 3 days max dose 1500 mcg 24 hr. Clearance hepatic and renal. Adverse effects may cause nausea, decreased GI motility, transient hyperglycemia, cholelithiasis, abdominal discomfort, headache, pain at injection site growth hormone suppression with long term use. Comments cyclosporine levels may be reduced.

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.

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).

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...

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...

Krzisnik Krk Longevity

Al-Regaiey, K.A., Masternak, M.M., Bonkowski, M., Sun, L., and Bartke, A. (2005). Long-lived growth hormone receptor knockout mice Interaction of reduced insulinlike growth factor 1 insulin signaling and caloric restriction. Endocrinology 146, 851-860. Bartke, A., Coschigano, K., Kopchick, J., Chandrashekar, V., Mattison, J., Kinney, B., and Hauck, S. (2001a). Genes that prolong life Relationships of growth hormone and growth to aging and lifespan. J. Gerontol. Biol. Sci. 56A, B340-B349. Bartke, A., Chandrashekar, V., Bailey, B., Zaczek, D., and Turyn, D. (2002). Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides 36, 201-208. Bartke, A. (2003). Can growth hormone (GH) accelerate aging Evidence from GH-transgenic mice. Neuroendocrinology 78, 210-216. Berryman, D.E., List, E.O., Coschigano, K.T., Behar, K., Kim, J.K., and Kopchick, J.J. (2004). Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Hormone & IGF Research...

Control of Gene Expression

The giant transgenic mouse on the left was produced by injecting a rat gene for growth hormone into a mouse embryo a normal-size mouse is on the right. To ensure expression, the rat gene was linked to a DNA sequence that stimulates the transcription of mouse DNA whenever heavy metals are present. Zinc was provided in the food for the transgenic mouse some transgenic mice produced 800 times the normal levels of growth hormone. (Courtesy of Dr. Ralph L. Brinster, School of Veterinary Medicine, University of Pennsylvania.)

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

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).

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.

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).

Gross Description

The body measured 122 cm in length and weighed 52 kg. In addition to short stature, the external exam revealed webbed neck, wide spaced nipples, underdeveloped clitoris, sacral and lower extremity edema and kyphoscoliosis. The pleural cavities contained 1.0 L each of straw-colored fluid. The pericardial sac contained also 30 cc of clear yellow fluid. The heart weighed 400 g with concentric hypertrophy and dilatation of the left ventricle (wall thickness 1.8 cm, normal up to 1.5 cm). The right ventricle wall measured 0.5 cm. The papillary muscles were hypertrophied and the

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).

Prader WilliAngelman Syndrome

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are characteristics of disorders resulting from genomic imprinting in which the phenotypic expression of the disorder depends on the parent from whom the genetic abnormality is inherited. Both syndromes involve structural or functional loss of expression of genes in the chromosome 15q11-q13 region, including deletions, uniparental disomy, and mutations in an imprinting center. Paternally inherited abnormalities result in PWS while maternally inherited abnormalities result in AS (Knoll et al., 1989 Ledbetter et al., 1981). PWS is characterized by developmental delay, hypotonia, and feeding problems in infancy followed by excessive and rapid weight gain resulting in severe obesity, cryptoorchidism, short stature, and mild MR. Behavioral characteristics include temper tantrums and ritualistic or obsessive-compulsive behavior (Clarke, Boer, Cheung, Sturney, & Webb, 1996 Dykens, Leckman, & Cassify, 1996 Webb et al., 2002). The...

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,...

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.

Umbilical artery Doppler velocimetry

Umbilical artery Doppler flow velocimetry is a technique of fetal surveillance based on the observation that flow velocity waveforms in the umbilical artery of normally growing fetuses differ from those of growth-restricted fetuses. The umbilical flow velocity waveform of normally growing fetuses is characterized by high-velocity diastolic flow, whereas with intrauterine growth restriction, there is diminution of umbilical artery diastolic flow. Abnormal flow velocity waveforms have been correlated with fetal hypoxia and acidosis and perinatal morbidity and mortality.

Designing Inhibitors Against New Targets

Proteins interact with other proteins, such as ligands with receptors, through large hydrophobic pockets. The hydrophobic pocket can be designed to identify small molecule ligands by mutagenizing the receptor and ligand interacting site to reduce their affinity 58 . A small-molecule indole-containing library was screened using a human growth hormone mutant receptor and mutant human growth factor ligand to find molecules that increased the binding affinity of the mutant receptor to mutant ligand. This strategy could be generalized to finding small molecules that modulate protein-protein interactions in a variety of cellular systems. In another strategy, disulfide-containing small-molecule ligands were tethered to the target protein of interest if the small molecule shows inherent affinity to the protein 59 . This method was validated by identifying a potent and selective inhibitor of thymidylate synthase.

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...

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