How to Grow Taller
Interest in the growth hormone insulin-like growth factor-1 (GH IGF-1) axis as a mediator of aging-related changes in the brain and other organ systems developed from the recognition that a substantial decline in serum GH and IGF-1 levels is one of the most robust hallmarks of mammalian aging (reviewed in 105-107 . Given the pleiotropic effects of IGF-1 in the brain and increasing evidence that GH has direct effects in the brain, as well as regulating IGF-1 levels, it is reasonable to expect that the aging-related decline in GH IGF-1 activity is significant for brain structure and function. There is experimental evidence that restoring GH and or IGF-1 in older animals ameliorates many aging-related neural changes (105, 107). With respect to neurogenesis, several lines of evidence implicate the GH IGF-1 axis in aging-related changes. The regulation of adult neurogenesis appears to be linked to the regulation of angiogenesis (e.g., 87, 90, 108 ), which is modulated in the aging brain by...
It is clear that a reduction in the testosterone concentration in healthy young individuals will result in a loss of fat-free mass and muscle strength 15 . It is also well-known that there is a reduction in testosterone of at least 1 per year after the age of 50 in normal healthy men 4 . Furthermore, it has been reported that reduced testosterone concentrations are related to reduced fat-free mass, appendicular skeletal muscle mass, and muscle strength in elderly individuals 16-19 . Additionally, growth hormone decreases with age. This results in a reduction in fat-free mass and an increase in visceral fat mass in the abdominal region 20-22 . An additional manifestation of the reduction in growth hormone is a reduction in circulating insulin-like growth factor (IGF)-1. Statistically significant inverse correlations have been observed between increasing age and IGF-1 concentrations 23 . It is believed that the effects of growth hormone on fat-free mass and fat mass are mediated through...
There are three studies that compared growth hormone (GH) administration with resistance training (RT) to RT alone. Yarasheski et al. 58 had men with low serum IGF-1 age 67 years complete 16 weeks of resistance training with GH administration or RT alone. They found no differences in the increase in the rate of vastus lateralis protein synthesis or isotonic and isokinetic strength between groups. Fat-free mass increased more in the RT + GH group than the RT group but this was attributed to an increase in non-contractile protein and fluid retention. Hennessey et al. 59 also reported no effect of GH administration with RT relative to RT alone with regard to strength improvements in elderly individuals (age 71.3 years). Strength improved by 55.6 in the GH + RT group and 47.8 in the RT alone group. Of possible importance, however, was the increase in the proportion of type II muscle fibres seen in the RT + GH group, as type II fibre atrophy and loss are observed in older individuals....
Growth hormone (GH) and insulin-like growth factor (IGF)-1 stimulate amino-acid uptake and protein synthesis in muscle and improve myocyte proliferation and differentiation in animal studies 106, 107 . The FDA recently granted accelerated approval for a form of recombinant human GH (rhGH) to treat AIDS wasting. Preliminary reports from Schambelan and co-workers in AIDS patients have all been positive 108-112 . The combined GH and IGF-1 doses used in studies in adult males with HIV-associated weight loss had mixed results in producing a sustained anabolic response 113-120 . In fact, after trauma, the anti-catabolic action of rhGH is associated with a potentially harmful decrease in muscle glutamine production and increased mortality 116 . Use of the rhGH for elderly patients with a low somatomedin C or IGF improved lean muscle mass, but not functional ability. Moreover, frequent side effects were seen 121 . Morley and coworkers 122 demonstrated that rhGH, which is a very expensive...
Human growth hormone, also known as somatotropic hormone, is secreted from the pituitary gland and is involved in many anabolic processes in the body including normal growth and tissue synthesis. Athletes have become more interested in the use of growth hormone (GH) in recent years because of the many reports touting its benefits, the increased awareness of the dangers of anabolic steroids, and the reduced price due to the increased availability of synthetic forms. The appeal to athletes is that GH stimulates amino acid uptake and protein synthesis in skeletal muscle and a degradation of fat in adipose tissue. It has been shown to increase fat-free mass and reduce body fat independent of diet and exercise. Nevertheless, these benefits do not come without side effects, including acromegaly (enlargement of bony structures in the extremities) and impaired glucose tolerance.
An added feature to bear in mind is that the preparation of certain medically important polypeptide drugs, such as human insulin and growth hormone, through genetic engineering methodologies, is well developed and convenient so these substances can be used in parenteral replacement therapy. Their preparation through synthetic peptide chemistry represents important achievements in peptide intellectual technology but does not satisfy a commercial need.
Express human genes, for example, in microbial, Escherichia coli or yeast, cells so that they manufacture proteins that medicinal chemists have not been able to synthesise they also produce hormones and autacoids in commercial amounts (such as insulin and growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and immune antibodies). Transgenic animals (that breed true for the gene) are also being developed as models for human disease as well as for production of medicines.
As suggested by the association between low serum insulin-like growth factor I (IGF-I) levels and loss of lean muscle mass, patients with CHF suffer from a clinically relevant imbalance between anabolic and catabolic influences on the peripheral muscle.49 In skeletal muscle biopsies of non-cachectic patients with CHF, the local IGF-I expression was substantially reduced despite normal growth hormone (GH) and IGF-I serum concentrations.50 It has been previously shown that a state of GH resistance may develop in cardiac cachexia. Exercise training has the potential to increase local IGF-I expression and to reverse muscle catabolism.
Measures introduced to increase blood safety may have the unintended consequence of decreasing blood availability. Results from demographic studies indicate that certain donor groups or donor sites present an unacceptable risk of disease transmission. For example, blood collectors no longer schedule mobile drives at prisons or institutions for the mentally disadvantaged because of the recognized high prevalence of transfusion-transmissible viruses in their residents. Few would argue the risk-benefit analysis of these exclusions. More questionable are the temporary exclusions of soldiers exposed to multiple tick bites at Fort Chaffee, Arkansas. Donors who have received human growth hormone injections have been indefinitely deferred because of the possible risk of transmitting Creutzfeldt-Jakob disease (CJD). However relatives of patients with 'sporadic' CJD are still deferred in the US (except for preparation of plasma fractions) despite evidence of their safety (Center for Biologics...
A unique property of the majority of eukaryotic mRNAs is their 3' poly (A) tail. This poly (A) tract is added posttranscriptionally by poly A polymerase after the nascent mRNA has been released from the transcription complex. The site of addition of the poly (A) tail is signaled by the presence of the sequence AAUAAA in the 3' untranslated region of the mRNA. The role of the poly A tail is not well understood, but is thought to be involved with export of the mRNA from the nucleus, prolonging the half-life of mRNA in the cytoplasm and enabling efficient translation (27). For construction of recombinant expression vectors, however, endogenous polyadenylation signal sequences are discarded and replaced by more generic elements. Two polyade-nylation signals commonly used in construction of mammalian expression cassettes are derived from SV40 (28) and bovine growth hormone gene (29). These sequences usually contain an AATAAA consensus sequence, which is 20-30 nucleotides 5' of a diffuse GT...
The importance of identifying robust, objective functional outcomes is recognised by regulatory bodies 47 . In approving growth hormone for the treatment of AIDS-related wasting, the American Food and Drug Administration (FDA) took account of an improvement in functional status reflected by an increase in treadmill work output compared with placebo 48 . It must be pointed out, however, that the relationship of laboratory-based tools such as the treadmill for assessing the capacity of patients to perform work bears an uncertain relationship to 'free-living' activity. The development of 'intelligent', ambulatory personal activity monitors (see below) may herald a new era in objective functional assessment in the patient's own environment.
Other atrophies of small, circumscribed areas of subcutaneous fat layers can appear after a local trauma or prolonged pressure, or at the site of drug (mainly of protein structure) injection. Extractive hormones, e.g. bovine insulin, growth hormone, ACTH, calcitonin, and vasopressin, have been reported to be responsible for this form of fat atrophy at injection sites. Local formation of immunocomplexes, or protein precipitate or activation of complement fractions could induce a local lipolytic response mediated by inflammatory agents, and may explain the zonal loss of subcutaneous fat. Tumour necrosis factor (TNF)-a release induced by insulin may mediate adipocyte atrophy 19 . An asymptomatic, discoid or funnel-shaped depression appears. Microscopic examination of biopsy samples of tissue from atrophic area shows the disappearance of fat cells. A dedifferentiation of fat cells to fibroblast-like cells can be postulated, rather than adipocyte necrosis. In fact, the subcutaneous fat may...
Other varieties of LD have been described in small series of patients. A syndrome characterised by a low birth weight, short stature, defective ocular development, mental retardation, delayed teething, hyperextensible joints, and atrophy of the subcutaneous fat layer at the arms and trunk, sparing any other site, called the SHORT syndrome, was reported by Sensenbrenner et al. in 1975 42 .
Transmembrane proteins occurs mostly near the plasmamembrane and is often blocked by metalloproteinase inhibitors, suggesting that metalloproteinases like MMPs or ADAMs are responsible for the cleavage. Inhibition of ectodomain shedding by metalloproteinase inhibitors is described for L-selectin (211, 212), CD44 (213) and CD43 (214), thyrotropin receptor (215), growth hormone receptor (216), c-erbB4 (217), low affinity nerve growth factor receptor (LNGFR) (218), IL-1RII (219), IL-6 receptor (220), the 55 and 75 kD TNF receptors (TNFR) (221, 222), proHB-EGF (223), TGFa (211, 224), TNFa (225, 226, 227), Fas ligand (228) and CD30 (229). Also serine proteinases are implicated in ectodomain shedding of some molecules like CD44 (213), CD43 (230) and IL-3 receptor (231).
Protein kinase C (PKC) is a key regulator of ectodomain shedding. Activation of PKC by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) results in a rapid stimulation of ectodomain shedding. Ectodomain shedding is stimulated by TPA for the adhesion molecules L-selectin (241, 242), intercellular adhesion molecule 1 (ICAM-1) (243), CD44 (213), MUC-1 (John Hilkens, personal communication), protein tyrosine phosphatases LARPTP (244, 119, 245) and PTPa (119), CD30 (229), growth hormone receptor (216) and the tyrosine kinase receptors c-erbB4
Growth hormone-releasing peptide-6 (GHRP-6) was the first peptidyl GHS able to release GH in vivo even after oral administration in humans 3, 4 . Further research led to the synthesis of other peptidyl and non-peptidyl GHS the spiroindoline MK-0677 was one of the most powerful, being able to enhance 24-h GH secretion and insulin-like
Each gene contains codes with instructions for the production of a specific protein -a chain of amino acids, each with a different function. Proteins can be transport molecules, antibodies, messengers, enzymes, hormones (such as growth hormone) or structural proteins. Genes contain 'promoters' and information blocks that read, accept or reject messages for gene activation for the creation of proteins. A gene in a rose petal will respond to a message to produce red pigment, but a palm leaf gene will block the same message. The genetic code of an organism describes the essential characteristics that will be inherited by each individual - the distinctive coloration of a neon tetra, the cold tolerance of a winter flounder, the toxicity of a cone snail. The entirety of the genetic information stored in an organism is called its genome.
In the mouse, several gene knockout strains have been serendipitously discovered to influence life span. For example, ablation of the ku86 locus yields mice that manifest a number of pathologies suggestive of premature senescence (18). Conversely, life span extension is observed in association with Pit1 and Prop1 mutations in the Ames and Snell dwarf mouse models, respectively. Homozygous defects at Pit1 or Prop1 loci compromise anterior pituitary development, leading to reductions in growth hormone, prolactin, and thyroid-stimulating hormone, as
In animals and humans, ghrelin has been reported to exert several biological activities such as (a) stimulation of growth hormone, prolactin and ACTH release (b) influence on the pitu-itary-gonadal axis (c) influence on sleep and behaviour (d) control of gastric motility and acid secretion (e) modulation of exocrine and endocrine pancreatic functions 14,66 .
In order to achieve a maximal possible suppression of endogenous insulin, glucagon and growth hormone release during hyperinsulinaemic clamp tests, a concomitant infusion of somatostatin can be applied (Gottesman etal. 1982 Best etal. 1983 Basu etal. 2000). Glucose clamp tests applying an infusion of somatostatin are commonly referred to as pancreatic clamp tests. Most investigators start the somatostatin infusion a few minutes before or simultaneously with the start of the insulin infusion. The infusion rates of somatostatin vary largely throughout the literature, ranging from 250 g per hour (Gottesman etal. 1982 Hawkins etal. 2002) to 360 g per hour (Henriksen etal. 2000) to 0.1 g-kg-1-min-1 (Krssak etal. 2004). One frequently reported side effect of high dose somatostatin infusions is abdominal discomfort. The use of somatostatin can be advantageous when stimulation of endogenous insulin secretion by substrates or pharmacological agents is to be minimised. One should be aware that...
Most patients affected by ectopic ACTH syndrome have malignant tumours, half of them being small-cell lung carcinoma. The metabolic manifestations appear suddenly and progress rapidly while the typical Cushing's habitus is absent. Anorexia, weight loss, and anaemia are frequent and comprise the picture of neoplastic cachexia 30,31 .
Another name for this hormone is somatotropin. Some people make too much or too little growth hormone. This can lead to disease. Too little growth hormone can cause a condition called pituitary dwarfism, meaning little growth. Children who do not make enough growth hormone are usually shorter than other children their age. They may have more fat around their stomachs and face, and lower-than-normal levels of sugar (glucose) in their blood. Adults who have damage to their pituitary gland may fail to make enough growth hormone. This condition, called adult growth hormone deficiency, causes weight gain, along with weak muscles and bones. If a child's body produces too much growth hormone, a rare disorder called gigantism results. Gigantism causes bones to grow very fast. The person becomes very tall. People who have gigantism have very large hands and feet, and thick fingers and toes. If the body produces too much growth hormone after a person stops...
The most common neoplasms associated with hypoglycemia are tumors of mesenchymal origin, such as mesotheliomas, fibrosarcomas, neurofibromas, spindle cell carcinomas and leiomyosarcomas. The most common mechanism involved in hypoglycemia is abnormal production of a precursor molecule to insulinlike growth factor (IGF) II, which is bound to insulin and IGF receptors, thus causing suppression of growth hormone secretion 8 .
As chemoattractants go, a plethora of proteins and agents have been shown to induce lymphocyte migration over the years, including complement components (e.g., C5a), PAF, eicosanoids (e.g., prostaglandin E2, leukotriene B4), bacterial-derived peptides (e.g., fMLP), endotoxin, growth factors (e.g., growth hormone), cytokines (e.g., IL-1a, TNF-a, IFN-y), and neuroendocrine hormones (e.g., opioids). Many of these chemoattractants not only induce lymphocyte migration but also facilitate lymphocyte adhesion to endothelial cells and purified adhesive ligands (36-42). This enhanced adhesiveness occurs within seconds of stimulation and, as with migration, is highly
A number of other techniques have been employed for the prevention or treatment of protein-energy malnutrition in dialysis patients. Routine methods include preventing protein-energy malnutrition before the onset of dialysis therapy, dietary counselling, maintenance of an adequate dose of dialysis, avoidance of acidaemia, and aggressive treatment of superimposed catabolic illnesses 56 . More novel, non-dietary interventions in addition to IDPN include an appetite stimulant such as megestrol acetate 174 , L-carnitine 175, 176 , and growth factors including recombinant human growth hormone (rhGH) 177 ,IGF-1 178 , and anabolic steroids 179 . Nonetheless, although
The analysis of interactions among endogenous chemical factors also needs to consider compensatory mechanisms that are activated during pro-catabolic activities or overriding anabolic processes. For instance, circulating ghrelin - a positive modulator of energy balance via orexi-genic, adipogenic and growth hormone releaser activities 39, 40 - levels are elevated in patients with wasting and cachexia and this elevation can be associated with increases in TNF-a 41 . The potential anti-cachectic activity of melatonin 42 is described by Lissoni et al. in Chapter 9.10.
Gene defects in humans can lead to deficiencies in proteins, such as insulin, human growth hormone, and Factor VIII that may result in problems, such as diabetes, dwarfism, and impaired blood clotting, respectively. Proteins for these chemicals can now be replaced by proteins manufactured through biotechnology. For insulin production, two protein chains are encoded by separate genes in plasmids inserted into bacteria. The protein chains are then chemically joined to form the final insulin product. Human growth hormone is also produced within bacteria, but special techniques are used because the bacteria do not usually produce human proteins.
Hormones Insulin, insulin-like growth factor-1 Growth hormone Megestrol Acetate and rhGH The metabolic effects of growth hormone (GH) and progestin derivatives, i.e. MPA and MA, are well-documented in humans. GH predominantly promotes positive nitrogen balance, increasing lean body mass (LBM) but simultaneously reducing fat body mass (FBM) 87-89 MA prevalently increases FBM, body water, and appetite 90, 91 . In AIDS-cachexia syndrome, there are important losses in LBM, FBM, and appetite 92-95 , but the administration of GH alone may be insufficient to correct metabolism disturbances that lead to this condition. We therefore tested whether improved results could be obtained with the combined use of GH and MA 71 .
Myoclonus epilepsy with ragged red fibers (MERRF) affects children and adults. Cardinal clinical manifestations include short stature, seizures, polymyoclonus, optic atrophy, sensory-neuronal hearing loss, cerebellar ataxia, peripheral neuropathy, and myopathy. The disease is maternally transmitted and is associated with point mutations in tRNA gene.
Many aspects of appetite regulation that involve peripheral signalling to hypothalamic pathways remain poorly understood. Growth hormone (GH) secretion from the anterior pituitary is regulated by GH-releasing hormone (GHRH), which stimulates the release of GH as well as its inhibitor somatostatin 76 . GH secretagogues are synthetic compounds able to stimulate secretion of the hormone 77 but which act through a receptor different from that for GHRH receptor. Instead, ghrelin was discovered to be the natural ligand for that receptor. Ghrelin is mainly secreted by gastric endocrine cells in the fundus into the systemic circulation 78 . Fasting increases, while feeding decreases circulating ghrelin concentrations 78 . These changes are negatively correlated with the serum concentrations of leptin and insulin.
The traditional role of the pharmaceutical industry, i.e. synthesis of new chemical entities as therapeutic agents, was suddenly expanded by the introduction of the first biotechnologically derived products in the 1980s. The approval of recombinant human insulin in 1982 broke important ground for products produced by genetic engineering (19). In 1985 another milestone was achieved when Genentech became the first biotechnology company to be granted approval to market a recombinant product, human growth hormone. These events set an entire industry into motion, to produce not only natural proteins for the treatment of deficiency-associated diseases, but also true therapeutics for both acute and chronic care.
Glucocorticoids enhance the lipolytic actions of other hormones, such as growth hormone, catecholamines, glucagon, and thyroid hormone. Gluco-corticoids also help in the mobilization of fatty acids from adipose tissues to the liver, where the metabolism of fatty acids inhibits glycolytic enzymes and promote gluconeogenesis. As a result of increased fatty acids oxidation,
The need for glycosylation of a recombinant protein is completely dependent on its effect on the efficacy (a function of biological activity and the clearance rate) of the protein in the patient. Bacteria typically do not glycosylate proteins, but can be utilized as hosts when efficacy is independent of glycosylation (for example, recombinant human insulin and human growth hormone). If the glycoform is critical for biological activity, the choice of the host organism becomes critical. All eukaryotic cells glycosylate proteins via common pathways however, evolution has imparted many variations. Therefore, the selection of a host for a glycoprotein is completely dependent of the biological in vivo activity of the therapeutic (1).
Pictures of a mentally retarded girl show the characteristic facial and skeletal features of the disease at ages 9 and 13 years. At age 13, she died of pulmonary infection. Note the short stature, large head, coarse facial features, thick tongue, and short neck. C. Transverse section of the brain shows dilated ventricles, focal thickening of the leptomeninges, and dilated perivascular spaces. D. Neuronal storage of PAS-positive material is moderate (PAS stain). E. The dilated pericapil-lary spaces are filled with a fine mesenchymal network (HE). Hurler's disease. A and B. Pictures of a mentally retarded girl show the characteristic facial and skeletal features of the disease at ages 9 and 13 years. At age 13, she died of pulmonary infection. Note the short stature, large head, coarse facial features, thick tongue, and short neck. C. Transverse section of the brain shows dilated ventricles, focal thickening of the leptomeninges, and dilated perivascular...
From a phenotypic view, many of the adolescent and adult patients with FA offer the impression of accelerated aging. These patients mostly are underweight individuals with short stature, a delicate body build, pale appearance, and a hoarse voice. They appear older than their biological age. Survival to age 50 year occurs only in rare instances, and many of the patients surviving to adulthood without bone marrow transplantation may in fact owe their relative longevity to self-correction of bone marrow cells manifesting as mosaicism. There is, however, the puzzle of rare patients with FA who appear phenotypically and clinically normal until adolescence and or adulthood, and who may only be diagnosed when their
In 1988, Harding and colleagues (44) and Wallace et al. (45) reported the first mitochondrial mutations causing human disease. Since then, many other mi-tochondrial diseases caused by mitochondrial point mutations or multiple mito-chondrial deletions have been identified (46). There are a number of typical presentations of mitochondrial disease in humans, including (1) Kearns-Sayre syndrome, characterized by ptosis, ophthalmoplegia, retinitis pigmentosa, hearing loss, cardiac conduction defects, short stature, and elevated cerebrospinal fluid protein (2) mitochondrial encephalopathy with lactic acidosis and strokes (MELAS) (3) myoclonic epilepsy with ragged red fibers (MERRF) (4) Leber hereditary optic neuropathy (LHON) with sudden unilateral or bilateral painless central visual loss and (5) Leigh syndrome, or subacute necrotizing en-cephalomyopathy. The pleiotropic manifestations of mitochondrial disease may include, for example, diabetes mellitus, hearing loss, bone marrow aplasia,...
Gelsolin and related proteins have been shown to be actively involved in normal embryonic development and morphogenesis as well as in pathogenesis of diseases such as amyloidosis and cancer. The gelsolin gene has been mapped to the chromosome 17p11.2 region, which is a critical region deleted in SMS which encompasses short stature, brachydactyly, dysmorphic features, retarded development, and behavioural problems. Gelsolin may also participate in the process of programmed cell death or apoptosis.
The pituitary gland is composed of two unique glandular tissues, the neurohy-pophysis and the adenohypophysis, which secrete a variety of hormones. The neurohypophysis or posterior pituitary stores and releases two main hormones produced in the hypothalamus, antidiuretic hormone (ADH) and oxytocin. The main function of ADH is in maintaining water balance and that of oxytocin is stimulation of uterine contractions during labor and breast milk ejection during lactation. The adenohypophysis or anterior pituitary provides a secondary level of control and stimulation of reproductive hormones through release of LH and FSH. Other pituitary hormones also may play a role in reproduction, including thyroid-stimulating hormone (TSH), growth hormone, and adrenocorticotropic hormone (ACTH). Thyroid-releasing hormone binds to plasma membrane receptors of cells in the pituitary gland to stimulate production and release of TSH, which in turn binds to receptors in cells of the thyroid gland to...
Physiological Disturbance in Cancer Cachexia Targets for Specialised Nutritional Therapy and Pharmacological
Physiologically, the breakdown of body tissue in cachexia reflects excessive catabolism and or inadequate anabolic activity. Persistence of these changes may eventually be detrimental to the patient's function and overall well-being. Possible mediators of catabolism are endogenous corticos-teroids, PIF, lipid-mobilising factor (LMF) and proinflammatory cytokines. Inadequate anabolic activity might reflect an impaired response to anabolic mediators such as anabolic-androgenic steroids, growth hormone or insulin or an inadequate supply of energy and macro micronutrients. For many patients with advanced cancer, alleviating cachexia by tumour cure is unfortunately not possible at this time. Therefore as the tumour persists so will the physiological disturbance and it seems likely that attempts to modulate cachexia with conventional nutritional supplementation alone will be unsuccessful.
Recently, leptin has been considered one of the main markers of nutritional status. Leptin is a cytokine-type peptide hormone that is produced mainly by adipocytes it decreases appetite and increases energy expenditure 63 . The effect of liver disease on leptin status is a controversial issue, although some studies have shown that serum leptin increases in cirrhosis of alcoholic aetiology 64, 65 . Currently, a high serum leptin concentration in cirrhotic patients is thought to result from the increased protein-bound fraction, which is directly related to energy expenditure 66 . Since ghrelin, which is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor, competes with leptin, it was also investigated in cirrhotic patients 67 . Tacke et al. reported that ghrelin increased in liver cirrhosis independent of its aetiology however, the precise mechanisms remain unclear 68 . Ghrelin might increase to counteract metabolic decompensation in liver cirrhosis by its...
Several endocrine abnormalities, such as low levels of testosterone and growth hormone and increased production of cytokines, have been correlated with weight loss in AIDS, while adrenal and thyroid hormones show conflicting patterns 63 . The synergic action of TNF and other cytokines is
Antithyroid drugs, by reducing thyroid hormone production, cause increased formation of TSH which is the cause of the thyroid enlargement that sometimes occurs during antithyroid drug therapy. GHRH and somatostatin both regulate growth hormone secretion. Sermorelin is an analogue of the hypothalamic growth hormone releasing hormone (somatorelin) it is used in a diagnostic test for growth hormone secretion from the pituitary. Somatostatin, growth hormone release inhibiting hormone, occurs in other parts of the brain as well as in the hypothalamus, and also in some peripheral tissues, e.g. pancreas, stomach. In addition to the action implied by its name, it inhibits secretion of thyrotrophin, insulin, gastrin and serotonin. Somatropin, growth hormone (Genotropin, Hum-atrope), is a biosynthetic form (191 amino acids) of growth hormone prepared by recombinant DNA technology, as is somatrem. Naturally occurring human growth hormone obtained from dead people is no longer used because of the...
The rat growth hormone gene has been cloned and transferred into mouse embryos, creating transgenic mice that at adulthood are twice normal size (see Chapter 29). Already, transgenic versions of domestic animals such as pigs, sheep, and even fish have been developed for human benefit. Perhaps most important, in a number of instances, clinical trials have been approved for gene replacement therapy (or, more simply, gene therapy) to correct particular human genetic disorders.
Growth hormone (somatrem, somatropin) and corticotrophin use may be combined with that of anabolic steroids. Chorionic gonadotrophin may be taken to stimulate testosterone production (and prevent testicular atrophy). Similarly, tamoxifen (antioestrogen) may be used to attenuate some of the effects of anabolic steroids.
Abbreviations used are ACTH, adrenocorticotropic hormone FSH, follicle stimulating hormone GH, growth hormone LH, luteininzing hormone PH, parathyroid hormone TSH, thyroid stimulating hormone EGF, epidermal growth factor, PDGF, platelet derived growth factor TGF, tranforming growth factor TNF, tumor necrosis factor GM-CSF, granulocyte-moncyte colony stimulating factor GABA, y-aminobutyric acid. Leukotrienes, prostaglandins, prostacyclines, thromboxanes Peptide hormones (ACTH, glucagon, growth hormone,
Four types of islet endocrine cells have been described according to the main hormonal content of their secretory granules beta-cells (insulin) accounting for 70-80 of total islet cells, alpha-cells (glucagon) accounting for 15-20 , delta-cells (somatostatin) accounting for 5 , and PP-cells (pancreatic polypeptide) accounting for 5 of total islet cells. These cells are derived from the epithelia of embryonic pancreatic ducts. In addition to their specific hormones, they also express numerous other peptides whose role is often unclear. Recently, a novel de-velopmentally regulated islet cell, the ghrelin cell, was identified in islets of human pancreas 6 . This cell is named according to the peptide it secretes. Importantly, ghrelin was not coexpressed with any known islet hormone. Ghrelin secretion is most prominent in the stomach and the peptide has been suggested to act as a hormone to release growth hormone from the pituitary 7 .
In 1982, Ralph Brinster of the University of Pennsylvania and Richard Palmiter of the University of Washington inserted a rat growth hormone gene into mouse embryos. Their experiment produced ''supermice'' that were twice as big as normal mice. Transgenic mice are still used to study diseases and their potential treatments
Other biologicals, such as tissue plasminogen activators (tPA), blood clotting factors, hormones, and polypeptide growth factors have been produced in vitro in serum-free cultures. Some examples of these processes include the production of tPA. In this serum-free system, cultures of fibroblasts on Cytodex-3 microcarriers gave yields comparable to that of 5 fetal bovine serum-containing media (134). Also, a serum-free culture of CHO cells in the production of recombinant human growth hormone allowed the elimination of a final purification step (135). The elimination of serum has allowed continuous nutrient optimization to improve the productivity (136).
For comparative studies, subjects should be age and gender matched, as there are important differences in counterregulatory responses between sexes and age groups (Matyka et al. 1997 Davis et al. 2000). Mixing genders and ages will at the very least increase the variance of the measures made and may obscure differences resulting from other factors. If groups are of mixed gender in a cross sectional study, the gender distribution must be matched. Vigorous exercise and caffeine should be avoided prior to the study as they can also affect counterregulatory responses (Debrah et al. 1996 Sandoval et al. 2006). Subjects should be studied in the same position (lying or standing) as there is a greater perception of hypoglycaemic symptoms in the standing position than in the lying position (Hirsch et al. 1991). It is usual to study subjects in the fasting or post-absorptive state. This allows a steady-state baseline. In the fed state, symptoms of hypoglycaemia are decreased, but...
GH (growth hormone), 379t, 389-390, 390t Graves' disease, 403, 408-410, 408t Gravimetric pipette calibration, 95 Growth hormone, action of, 379t Growth hormone (GH) action of, 379t, 390t secretion of, disorders of, 390 source of, 390t synthesis of, 389-390 Growth hormone-releasing hormone (GHRH), 389t Growth retardation, in growth hormone
Stimulation of the nicotinic cholinergic receptor causes the release of many different neurotransmitters including acetylcholine, norep-inephrine, dopamine, serotonin, beta-endorphin, gamma-aminobutyric acid, and glutamate. It also causes the release of hormones such as growth hormone, prolactin, vasopressin, and adrenocor-ticotropic hormone (ACTH).8
The role of IL-1 in the pathogenesis of CACS has been clearly elucidated. IL-1 exerts a specific effect on reducing food intake and influences meal size, meal duration and meal frequency 14, 15 . Hypothalamic IL-1 is increased either through access from the median eminence (a cir-cumventricular nucleus without a blood-brain barrier proximal to the arcuate nucleus) or is generated within the hypothalamus 16 . IL-1 has an anorectic action by directly decreasing neuropep-tide Y (NPY) neurotransmission and secondarily by increasing corticotropin-releasing factor (CRF), which in turn acts on the satiety circuitry inhibiting food intake. In rat models, IL-1 has been demonstrated to inhibit serum levels of growth hormone (GH) by increasing CRF and somatostatin levels 17 . The reduced synthesis of GH leads to reduced synthesis of the insulin-like growth factors (IGFs), which in turn influence the muscle protein turnover and the autocrine and paracrine regulation of muscle mass proliferation...
Since the acylation of ghrelin is required for the activation of the type 1a growth hormone sec-retagogue-receptor (GHS-R), it was assumed that des-acyl ghrelin was void of endocrine properties 13 . The des-acyl ghrelin showed no effect on the elevation of intracellular Ca2+ concentrations in cells that express the GHS-R and for increasing plasma GH concentrations in rats 14,15 . Later, a paper reported that des-acyl ghrelin is able to antagonise the metabolic but not the neuroendocrine response elicited by acylated ghrelin in humans 16 . Serum GH levels correlated closely with plasma acylated, rather than des-acylated ghrelin 17 . However, transgenic mice overex-
Spinal RT (CrSp) in this group are considerable, and include secondary hypothyroidism, growth hormone deficiency, and in girls, either precocious puberty or incomplete pubertal development, as well as risking infertility from irradiation of the hypothalamus, pituitary, and ovaries. Irradiation to the vertebrae will result in failure of these bones to grow during the adolescent growth spurt, causing loss of up to 5 cm in height this is unresponsive to growth hormone therapy.
Late effects among survivors of AML during childhood and adolescence may have a significant impact on their quality of life. Long-term sequelae of treatments can include impaired intellectual and psychomotor functioning, neuroendocrine abnormalities, impaired reproductive capacity, and second malignancies 44 . However, most of these late effects, especially side effects after CNS irradiation (neurocognitive deficits, growth hormone deficiency, and secondary CNS tumor) given in the AML-BFM studies for all age groups, but not in other AML trials, affect the younger age group. Anthracycline cardiotoxicity is also seen at lower cumulative doses (
The clinical course of the disease appears to be much more strongly determined by the type of mutation and ethnicity rather than by belonging to a given complementation group (22,23). For example, the IVS4+4A T mutation in the complementation group C gene causes early onset of hematological symptoms and consistent short stature combined with radial ray defects, whereas the 322delG mutation in the same gene usually causes fewer somatic abnormalities and a much later onset of aplastic anemia (24). There are some indications that patients belonging to complementation group G and patients homozygous for null mutations in the complementation group A gene may have a more unfavorable clinical course (25), but definitive genotype-phenotype correlations require prospective studies.
The large-scale production of proteins using cDNA-based expression systems has wide applications for medicine and industry. It is increasingly being used to produce polypeptide-based drugs, vaccines, and antibodies. Such protein products are called recombinant because they are produced from a recombinant plasmid. For a mammalian protein to be synthesized in bacteria its cDNA must be cloned into an expression vector (as described on page 139). Insulin was the first human protein to be expressed from a plasmid introduced into bacterial cells and has now largely replaced insulin from pigs and cattle for the treatment of diabetes. Other products of recombinant DNA technology include growth hormone and factor VIII, a protein used in the treatment of the blood clotting disorder hemophilia. Factor VIII was previously isolated from donor human blood. However, because of the danger of infection from viruses such as HIV, it is much safer to treat hemophiliacs with recombinant factor VIII. It...
Two of the pituitary hormones stimulated by fenfluramine and buspirone are prolactin and growth hormone. There is some evidence that CFS patients have an increased buspirone-stimulated prolactin release when compared to controls (Bakheit et al. 1992 Sharpe et al. 1996a). One study also demonstrated a reduced growth hormone response to hypoglycaemia in CFS patients when compared to controls (Allain et al. 1997), but this finding is not consistent (Sharpe et al. 1996a).
Reduced production of sexual hormones by the gonads is the most obvious manifestation of endocrine senescence and may affect development and growth of hormone-dependent tumors, such as prostatic, mammary, and endometrial cancer. It is important to remember that the activity of sexual hormones is also influenced by body size and shape. With aging, abdominal deposition of fat becomes more common and is associated with increased aromatization of androgens and circulating levels of estrogens (17). In addition, abdominal obesity is associated with decreased concentrations of sexual hormone-binding proteins in the circulation (17). For this reason, obesity may favor the development of breast cancer in postmenopausal women and favor its recurrence after surgery. Obesity may also be associated with increased insulin resistance, increased circulating levels of insulin and, consequently, of growth hormone and of insulin-like growth factor 1 (IGF-1), that is, a powerful growth stimulator of...
NPY in the hypothalamus and consequently removes the inhibitory action of NPY on growth hormone-releasing hormone (GHRH) release. Leptin stimulates the synthesis and release of luteinising hormone and follicle-stimulating hormone in animals. Ovarian follicular cells are regulated directly by leptin, indicating that it is able to control the hypothalamic-pituitary-gonadal axis at multiple levels 79, 80 . These results show that leptin is not only an adipostat signal, but it acts as a metabolic switch, informing the brain when fat reserves are adequate to direct energy expenditure towards activities other than seeking calories 37 .
The hormonal counterregulatory response to hypoglycaemia is a carefully orchestrated release of hormones that has a natural hierarchy in the non-diabetic individual that protects the individual from severe hypoglycaemia (Mitrakou et al. 1991). The first step is a reduction in insulin production, followed by the release of glucagon, adrenaline, cortisol and growth hormone (Cryer et al. 1989).
Most experimental hypoglycaemia is induced by insulin. An intravenous insulin challenge, called the insulin tolerance or insulin stress test, was the first test used to determine the effect of hypoglycaemia (Dell'acqua 1951 Hanzlicek & Knobloch 1951). This method was used in early studies that identified the role of the adrenal gland in protective responses to hypoglycaemia (Vogt 1951 De Pergola & Campiello 1953) and has also been used in the past to induce hypoglycaemic seizures as a treatment for severe depression (Mueller et al. 1969) and as a stimulus for gastric acid secretion in the standard Hollander test assessing the completeness of vagotomy (Colin-Jones & Himsworth 1970). It is still used to determine pituitary reserve for growth hormone and cortisol release.
, adipose tissue is distributed'widely in animal bodies, comprising large cells (fat cells) each with single large fat droplet inside a thin rim of cytoplasm. This depot fat is composed largely of triglyceride. ,ad -renaline, glucagon, growth hormone and acth all stimulate release ot_ tatty acids and glycerol via activation of intrinsic lipases proBably via cyclic AMP (see amp, second messenger) .
Cancers generally retain characteristics that reflect their origin. One type of skin cancer called basal-cell carcinoma is derived from ker-atinocytes and will continue to synthesize keratin, the protein of hair and nails. Another form of skin cancer, called melanoma, is derived from pigment cells, and is associated with overproduction of the skin pigment melanin. It is for this reason that these tumors are usually very dark in color. Cancers of the pituitary gland, which produces growth hormone, can lead to production of excessive amounts of this hormone, the effects of which can be more damaging than the cancer itself.
In health, the human body protects itself from clinically important hypoglycaemia very efficiently through a series of physiological and neuroendocrine responses, collectively described as 'counterregulation' (Amiel & Gale 1993). The major components of the counterregulatory hormone responses are shown in Figure 5.1. Blood glucose concentrations are normally very strictly regulated at 3.5-7 mmol l despite massive fluctuations in the rates at which tissues utilise glucose (rest vs exercise) and glucose is entering the circulation (fed vs fasted). It is important to remember that the systems we describe as 'counterregulatory' in the sense that they defend against hypoglycaemia, are in fact 'regulatory' and teleologically are present to maintain normality in health, not defend against pathology or iatrogenic disease. The regulatory mechanisms that are activated by any threat to blood glucose supply start with reduction in endogenous insulin secretion and increased release of pancreatic...
Arginine is a semi-essential amino acid important to the urea cycle, and supports the synthesis of other amino acids and of polyamines, urea and NO 62 . Arginine is important for cell-mediated immunity, and exogenous sources are often required during sepsis. The growth and function of T lymphocytes in culture requires l-arginine. In vivo, arginine has the effect of retarding thymic involution by encouraging production of thymic hormones and thymocyte proliferation. Arginine also promotes leukocyte-mediated cytotoxicity in a number of ways. Growth hormone receptors are widespread in the immune system, and arginine may increase the cytotoxic activities of macrophages, NK cells, cytotoxic T cells, and neu-trophils by releasing growth hormone. A product of arginine metabolism, NO, has tumoricidal and microbicidal activities, induces blood vessel dilatation, and influences leukocyte-endothelial cell adhesion.
A transgenic animal is produced by introducing a foreign gene into the nucleus of a fertilized egg (Fig. 7.16a). The egg is then implanted into a foster mother and the offspring are tested to determine whether they carry the foreign gene. If they do, a transgenic animal has been produced. The first transgenic mice ever made were used to identify an enhancer sequence that activates the metallothionein gene when an animal is exposed to metal ions in its diet. The 5' flanking sequence of the metallothionein gene was fused to the rat growth hormone gene (Fig. 7.16ft). This DNA construct, the transgene, was injected into fertilized eggs. When the mice were a few weeks old, they were given drinking water containing zinc. Mice carrying the transgene grew to twice the size of their litter mates because the metallothionein enhancer sequence, stimulated by zinc, had increased growth hormone production.
A general chronology of growth hormone-releasing peptide (GHRP) and ghrelin and their shared receptor is shown in Table 1 1-3 . The discovery of the natural hormone ghrelin appears to be the exciting beginning of a new unusual hormone system. Initially, in 1980, GH-releasing activity of the unnatural GHRPs was thought to represent the activity of the as-yet unidentified natural hypophysiotrophic hormone GH-releasing hormone (GHRH). However, in 1982, GHRH was isolated from a pancreatic tumour and the hypothalamus and chemically identified as 44 and 40 amino acid linear peptides. Although the GH-releasing activity of GHRPs and GHRH are similar, it is also apparent that they are definitely chemically and functionally different because of the uniqueness of the action of GHRP on GH secretion in vitro as well as in vivo in a variety of animal species. In 1984, it was postulated that GHRP reflected the activity of another new hypothalamic hormone involved in the increased secretion of GH and...
Two proteins identified in the survey, termed ALMS1 and OFD1, have previously been identified genetically as being linked to human diseases. In particular, the C-terminal half of ALMS1 was localized to the centrosome by tagging 21 and, independently, antibodies to OFD1 have been shown to decorate the centrosome 31 . Both proteins need further investigation to confirm their association with the cen-trosome but their identification as candidate centrosome components is intriguing. The diseases caused by defects in these genes are relatively rare and poorly understood. Patients with Alstrom syndrome (ALMS1) display a complex set of symptoms. Childhood obesity starts at the early age of 6 months and many patients develop type 2 diabetes. The disease is also associated with neurosensory defects and subsets of patients show dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild developmental delay 32, 33 . The symptoms of oral-facial-digital...
The earliest signs that are suggestive of a diagnosis include failure to thrive, alopecia, and subcutaneous skin changes suggesting scleroderma. Variable degrees of insulin resistance and inconsistent abnormalities of serum cholesterol and other lipids are found, but there are no demonstrable abnormalities of thyroid, parathyroid, pituitary, or adrenal function. We studied five cases of progeria and found 24-hr growth hormone levels to be normal, but reduced levels of insulinlike growth factor I and markedly increased basal metabolic rates were found, suggesting a profile of bioinactive growth hormone (35).
It is important that every underweight patient at risk for malnutrition undergoes intense nutritional support in order to improve the prognosis of the underlying disease as well as the quality of life. The patient's ability to maintain his or her weight at close to ideal or normal levels may be aided by the prescription of appetite-stimulating drugs (Table 2), such as cyproheptadine 63, 64 , medroxyprogesterone acetate (MPA) 65, 66 , megestrol acetate (MA) 67-69 , insulin-like growth factor-1 (IGF-1) 70 , corticosteroids, and growth hormone 71,72 .
The subjects ranged in age from 21 to 77 years with a median age of 43 years. Twenty-five individuals were Caucasian and 20 were Black. Twenty percent of the individuals had age-matched z-scores in the spine of -1 or poorer, whereas only 8.8 had similar age-matched z-scores in the proximal femur. Osteopenia in the spine was correlated with duration of disease and hypogonadism. Total body calcium was increased even in osteopenic patients suggesting that excess growth hormone insulinlike growth factor-1 (GH IGF-1) caused a positive bone balance except in the spine. Thirteen percent of subjects in this study had BMD values in the spine that were two or more SDs above the age-matched mean BMD value.
Growth hormone was discovered in the 1920s. About thirty years later, scientists figured out how to remove growth hormone from the human pituitary gland. They gave it to children with growth hormone deficiencies and discovered it helped them grow. This discovery led to the development of growth hormone replacement therapy. The first growth hormone replacement therapy medicine was taken from the pituitary glands of dead bodies (cadavers). It was given through a shot (injection). Between 1958 and 1985, the medicine was used to treat more than 8,000 children with growth hormone deficiencies. In 1985, scientists discovered that some people who had received the growth hormone made from dead bodies developed a deadly brain disorder called Creutzfeld-Jakob disease. The U.S. Food and Drug Administration (FDA) said that the medicine could no longer be sold. Scientists started looking for new ways to create growth hormone medicine. The first artificial (synthetic) human growth hormone, called...
Endocrinological these tumors are characterized by elevated production of somatotrophic hormone (STH). The excessive production of growth hormone produces in (preferentially male) children and adolescents with as yet unclosed epiphyses accelerated growth of long bones that can lead to gigantism, whereas among adults (here the female sex is more commonly affected) the effect is to produce acromegaly enlargement of the acral body parts -nose, chin, fingers and toes with enlargement also of abdominal organs and a deepening of the voice. The treatment of STH-producing tumors must take a surgical approach, which can usually be done by a trans-sphenoidal approach (see Chap. 22). For intrasellar tumors, the success rate approaches 90 . In cases where surgery is not possible, analogs of somatostatin are an effective alternative. These agents can normalize the STH levels in 90 of cases, improve the symptoms in 50 of cases, and reduce the size of the tumor in 44 of cases. Initial studies of...
The GH3 cell line was derived from the pituitary tumour of a 7-month-old female Wistar-Furth rat (Tashjian et al, 1968) and is used for the study of hormones. The GH3 clone produces growth hormone at a greater rate than GH1 cells, a clone obtained from the same primary culture, and also produces prolactin. Hydrocortisone can be used to stimulate hormone production and also inhibits the production of prolactin (Bancroft et al, 1969). The cells are epithelial-like in morphology but can be adapted to grow in suspension culture using Eagle's MEM,
Events, and lack of downstream processing data. Many recombinant proteins have been expressed in plants. Therapeutically important recombinant proteins that have been expressed in transgenic plants include EPO, growth hormone, and hirudin. However, it does not appear that the glycosylation of these proteins was examined (40). Also, if sialic acid is required for efficacy, transgenic plants may not be well suited, since only buckwheat has been reported to produce sialic acid (10,41,42). Additionally, plants may produce antigenic sugars residues like a1,3-Fuc and Xylb1,2-Man (42,43). Transgenic plants could provide an important alternative for the production of recombinant proteins, where glycosylation and sialylation are not required. More research is needed to fully characterize the capability of transgenic plants to glycosylate therapeutic proteins.
An impressive example of a systematic search for a binding epitope is seen in the work used to define the human growth hormone-somatogenic receptor interaction (60, 61). First, using a technique termed homologscanning mutagenesis, segments of sequences amino acids in length) from homologous proteins known not to bind to the hGH receptor or to hGH-sensitive monoclonal antibodies (Mab) were systematically substituted throughout the hGH structure by using a working model based on the three-dimensional folding pattern found by X-ray crystallographic analysis of the highly homologous porcine growth hormone (62). Using an enzyme-linked immunosorbent assay (ELISA)-based binding assay, which measures the affinity of the mutant hGH for its re-combinantly derived receptor, researchers discovered that (63) swap mutations that disrupted binding were found to map within close proximity on the three-dimensional model, even though the residues changed within each subset were usually distant in the...
The nature of consciousness is still a mystery, but has never been of more fascination to scientists, whether psychologists, physiologists, or physicists. While there may be disagreement over the epistemological status of awareness, people are generally agreed that it is a state involving self-referential activity. Consciousness involves the knowledge that one is conscious it is a reflective state that even reflects itself, and we could picture it as some sort of mirroring process. This is one aspect of the age-old puzzle of what consciousness is. An old-fashioned way of picturing awareness was to propose that our sensations are perceived by a homunculus (little man) located inside our head who views the sensory input coming in to the brain like someone watching a television set. The question naturally arises of how the homunculus does his perceiving. Does he have eyes inside his head looking at his incoming sensations on a yet smaller screen The problem was in this way pushed a stage...
Table 2a. 30-Day continuous subcutaneous infusion of 1 g kg h growth hormone-releasing peptide (GHRP)-2 Table 2a. 30-Day continuous subcutaneous infusion of 1 g kg h growth hormone-releasing peptide (GHRP)-2 Age 64 2.8, BMI 26 1.1, n 17, values are mean of single determinations at end of infusion, p value a 0.001,b 0.01. IGF, insuline-like growth factor GH, growth hormone Table 2b. 30-Day continuous subcutaneous infusion of 1 g kg h growth hormone-releasing peptide (GHRP)-2 Table 3. In vitro active growth hormone-releasing peptides Table 4. In vivo active growth hormone-releasing peptides (GHRPs)
There are four approved drug products for the treatment of cachexia oxandrolone, dronabinol, megestrol acetate and growth hormone. Oxandrolone, an anabolic steroid, is used to promote weight gain and offset protein catabolism. Dronabinol and megestrol acetate were approved initially for the anorexia associated with human immunodeficiency virus (HIV) acquired immunodeficiency syndrome (AIDS) and since have been used to treat anorexia associated with cachexia. Growth hormone has been shown to produce a positive change in lean body mass in clinical trials. However, these drug products have not been studied intensively in cancer patients, and none has been approved for cancer cachexia 12,13 .
Polypeptide (and most abundant) hormone of anterior pi tu tary . Regulates deposition of collagen and chondroitin sulphate in bone and cartilage promotes mitosis in osteoblasts and increase in girth and length of bone prior to closure of epiphyses. Transported in plasma by a globulin protein. Its release is prevented by hypothalamic somatostatin. Induces release from liver of the hormone somatomedin, which mediates its effects at the cell level. Low levels in man result in dwarfism, high levels in acromegaly.
In hypopituitarism there is a partial or complete deficiency of hormones secreted by the anterior lobe of the pituitary. The posterior lobe hormones (see below) may also be deficient in a few cases, e.g. when a tumour has destroyed the pituitary. Patients suffering from hypopituitarism may present in coma, in which case treatment is as for a severe acute adrenal insufficiency. Maintenance therapy is required, using hydrocortisone, thyroxine, oestradiol and progesterone (in women) and testosterone (in men). For growth hormone see above.
Protein anabolism is increased by androgens, i.e., androgens increase the proportion of protein laid down as tissue, especially muscle (and, combined with training, increase strength). Growth of bone is promoted, but the rate of closure of the epiphyses is also hastened, causing short stature in cases of precocious puberty or of androgen overdose in the course of treating hypogonadal children.
Let's now try to build a modern-day equivalent of Wallace's statement. It will not rival the elegance of his words, but it will help to give a more complete understanding of this general world view, which is still so prevalent today. A good starting point is human height. This is often used in genetics texts to illustrate the phenomenon of continuous (as opposed to discrete) variation. If we plot the frequency distribution of adult males or adult females for the human population of, say, Iceland, we will get the familiar bell-shaped or 'normal' curve with most values close to the average and fewer further away, as shown in Figure 11 (top). Admittedly, character distributions
Anabolic agents shift the anabolic catabolic balance of protein metabolism toward the synthesis of new proteins, which is needed to replace the proteins that are continuously catabolized, therefore maintaining muscle integrity and volume. Hypertrophy requires the proliferation of muscle nuclei (hyperplasia) in order to maintain the nuclear cytoplasmic ratio (52). Hormonal factors shown to be related to muscle hypertrophy are Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), testosterone and dehydroepiandrosterone. High IGF-1 concentrations are associated with characteristics that are opposite to those typical of aging, including decreased body fat content, increased muscle mass and improved metabolic homeostasis of glucose and lipids. At the muscular level, IGF-1 stimulates protein synthesis and satellite cell differentiation, thus, playing a crucial role in the maintenance of muscle mass and function. Many studies have provided insight into the signaling pathways by which...
Allelic substitutions at such loci tend to have little individual effect upon phenotypic differences between individuals, the normal situation in much of developmental biology, where expression of several different genes is required for production of a character. Such polygenic inheritance increases the likelihood that a character will exhibit continuous v ar i a ti o n in the population. Human height is an example. Compare pleiotropy, epi-
The anterior lobe secretes at least seven hormones. One hormone, the human growth hormone (HGH), promotes body growth by accelerating protein synthesis. This hormone is also known as somatotropin. A deficiency of the hormone results in dwarfism an oversecretion results in gigantism.
A 26-year-old woman presents to the emergency room complaining of sudden onset of palpitations and severe shortness of breath and coughing. She reports that she has experienced several episodes of palpitations in the past, often lasting a day or two, but never with dyspnea like this. She has a history of rheumatic fever at age 14 years. She is now is 20 weeks pregnant with her first child and takes prenatal vitamins. She denies use of any other medications, tobacco, alcohol, or illicit drugs.
Pharmacological Effects of Ethanol on the Nervous System, 1996, Richard A. Deitrich Immunopharmaceuticals, 1996, Edward S. Kimball Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant Experimental Models of Mucosal Inflammation, 1995, Timothy S. Gaginella Human Growth Hormone Pharmacology Basic and Clinical Aspects, 1995,
Serum hormones stimulate breast growth during pregnancy nipple growth is related to serum prolactin levels areolar growth is related to serum placental lactogen (Cregan & Hartmann, 1999). Estrogen and progesterone also exert their specific effect on the breast during pregnancy the ductal system proliferates and differentiates under the influence of estrogen, whereas progesterone promotes an increase in size of the lobes, lobules, and alveoli. Adrenocorticotropic hormone (ACTH) and growth hormone combine synergistically with prolactin and progesterone to promote mammary growth.
Y-hydroxy butyrate (GHB) is a naturally occurring substance in the human brain structurally related to GABA that may be a neurotransmitter (100). It has been used as an anesthetic (although it has little analgesic effect), to alleviate narcolepsy, and to treat alcohol and opiate dependence (101). There have been reports of abuse in the United Kingdom and United States within the dance scene and gay clubs and with body builders because it is said to promote slow-wave sleep during which growth hormone is secreted (102). It is available as a colorless, odorless liquid, powder, or a capsule to be taken orally it is rarely injected. GHB is rapidly absorbed, with peak plasma concentrations occurring 20-45 minutes after oral administration. It has a half-life of 30 minutes (103), and effects can last from 45 minutes to 8 h (104).
In addition to autonomic nerves, many circulating factors (humoral substances) exist that affect cardiac and vascular function. Some of these humoral factors directly influence the heart and blood vessels, whereas others indirectly alter cardiovascular function through changes in blood volume. Major humoral factors include circulating catecholamines, the renin-angiotensin-aldosterone system, atrial natriuretic peptide, and antidiuretic hormone (vasopressin). Although not addressed in this chapter, note that many other hormones and circulating substances (e.g., thyroxine, estrogen, insulin, and growth hormone) have direct or indirect cardiovascular effects.
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