How to Grow Taller
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...
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....
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...
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,...
In 1973 Brazeau, et al. reported the isolation and chemical and biological characterization of somatotropin-release inhibiting factor (SRIF-14, somatostatin). At one of the regular meetings of all the department heads, both chemists and biologists, Dr Sarett asked whether there were any ideas that could serve as the basis for a novel antidiabetic program. I was aware of the studies by Dr Luft and his team at the Karolinska Institute that growth hormone (GH) may play a permissive role in the development of retinopathy in diabetes. In addition, Dr Unger47 pointed out that while glucagon levels are within the normal range in diabetics, they are inappropriately high if one considers the plasma levels of glucose in these patients. Because SRIF-14 suppresses both GH and glucagon release, I had become interested in finding an analog of SRIF-14 with a half-life sufficiently long to test the concept that lowering both GH and glucagon levels in diabetics would be beneficial. Since SRIF-14 also...
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...
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...
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 psycho-motor 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 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).
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...
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...
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 .
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
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...
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...
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
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-
The era of follow-on biopharmaceuticals has arrived. A number of early biopharmaceuticals that lost patent protection in 2006 are already in production by noninnovator companies (Walsh 2003a). Some of the follow-on bio-logics currently on the market include human growth hormone and alpha-interferon in eastern Europe, and colony stimulating factor in China (Walsh 2003a).
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
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.
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 .
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 .
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...
One of the first genetically engineered products available to farmers was bovine somatotropin (BST), also called bovine growth hormone (BGH). Made naturally in the pituitary gland of cattle, the hormone promotes growth in calves and regulates milk production in mature dairy cows. The engineered version of the hormone is used to increase a cow's milk yield by up to 20 percent. It is manufactured by bacteria using copies of the cow's genes, so the product administered to the cow is essentially the same as that made by the cow herself. Nonetheless, the use of recombinant BST has been the subject of heated controversy since the mid-1980s, and the battle for public opinion still continues. Ironically, further developments in genetic engineering may move the long-running debate over bovine growth hormone into new pastures. Cows could eventually be genetically altered so they produce more BST themselves, eliminating the need to inject the synthetic hormone.
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.
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
Hormones Insulin, insulin-like growth factor-1 Growth hormone 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 .
Dynamic pituitary testing was performed with 100 g of GnRH and 25 g of arginine. FSH, LH, prolactin, and growth hormone (GH) responses were within normal limits. Therefore, functional hypothalamic amenorrhea (FHA) was diagnosed. She was placed on a daily dose of 1.25 mg of conjugated equine estrogens (CEE) and a cyclic dose of 10 mg of medroxyprogesterone acetate for days 1-12 of each month. Normal menstrual flow was established with this dose regimen.
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.
Several lines of evidence support the hypothesis that GHB is a neurotransmit-ter. GHB temporarily suppresses the release of dopamine in the mammalian brain. This is followed by a marked increase in dopamine release, accompanied by the increased release of endogenous opioids (Hechler, Goebaille, & Maitre, 1992). GHB also stimulates pituitary growth hormone (GH) release, although the mechanism by which GHB stimulates GH release is not known. Dopamine activity in the hypothalamus stimulates pituitary release of GH, but GHB inhibits dopamine release as it stimulates GH release. While GH is being released, serum prolactin levels also rise in a similar, time-dependent fashion. GHB has several different actions in the CNS, and some reports indicate that it antagonizes the effects of marijuana (Galloway et al., 1997). The consequences of these physiological changes are unclear, as are the overall health consequences for individuals who use GHB.
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
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
IGF-1 and -2 are weaker mitogens for osteoblast precursors and also promote initial differentiation. Their physiologic role is in part to mediate the anabolic actions of growth hormone. They have modest anabolic effects on bone when given systemically, though dosing tends to be limited by agonist actions on the insulin receptor at higher circulating concentrations.
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.
Young adult cancer survivors may also have reduced bone density, as measured by dual energy x-ray absorptiometry (DEXA) scans 117-119 . Although several studies have demonstrated decreased bone density at diagnosis in patients with ALL 120 , osteopenia and osteoporosis are well-recognized to progress following exposure to corticosteroids or radiation therapy in doses used in patients with soft-tissue sarcomas or Ewing sarcoma 116 . Osteopenia in ALL survivors, as documented by quantitative computed tomographic scans, has also been related to cranial irradiation 121 . Exposure to radiation at a dose less than 25 Gy may result in osteopenia significant enough to cause spontaneous fractures, but which may go undetected by plain radiographs. Antimetabolites have been linked to decreased bone density in a manner that appears to be dose dependent. Following methotrexate, this problem appears primarily during therapy and resolves once the drug has been discontinued 122 . Both genders are at...
Study, Oeffinger et al. observed cardiovascular disease risk factors such as obesity, dyslipidemia, hypertension, and insulin resistance in 62 of a cohort of young adult survivors treated for ALL in association with sedentary activity levels 37 . The higher prevalence of obesity in survivors treated with cranial radiation has been attributed to lower physical activity and resting metabolic rate, and hormonal insufficiency 32 . In particular, hypothalamic insult may predispose to obesity through leptin insensitivity 39 and adult growth hormone deficiency, which is associated with higher rates of dyslipidemia, insulin resistance, and cardiovascular mortality 40, 41 .
22.214.171.124.1 Growth hormone secretagog receptor agonists Ghrelin is the endogenous ligand for the growth hormone secretagog receptor. In addition to its well-described role in regulating pituitary growth hormone release, this receptor is expressed on motor neurons in the enteric nervous system and there is increasing evidence that activation of these receptors can increase GI motility. Ghrelin administration increases gastric emptying in an animal model of gastroparesis,101 an effect that has been replicated in healthy human subjects102 and in patients with either idiopathic103 or diabetic gastroparesis,4 where administration of human recombinant ghrelin enhanced gastric emptying.
Over the past 20 years, the biotechnology industry has been extraordinarily successful in bringing a wide variety of new products to the market. It is often perceived that the biotechnology industry has been faster than the traditional pharma industry in bringing products to the market. However, the list (from insulin through growth hormones and gonadotrophins, to EPO) shows that the road in the early days was often long and difficult, and started from an 'in vivo' demonstration of activity using crude extracts (Fig. 17.2). Indeed, the majority of the early products of biotechnology were proteins from natural sources (insulin, growth hormone) purified based on biological activity subsequent protein sequencing was obtained, thus allowing cloning from cDNA libraries only when the recombinant DNA technology became available in the late 1970s. The triumph of the biotech industry has been in finding ways to produce the molecules on a large scale, and at a quality that allows their safe...
This 33-yr-old man presented with recurrent kidney stones and hypercalcemia, and was diagnosed as having primary hyperparathyroidism (serum Ca 10-12 mg dL, serum PTH 95 pg mL). Further work-up demonstrated a growth hormone and prolactin secreting pituitary tumor, a spinal cord ependymoma, and an insulinoma therefore, a diagnosis of MEN 1 Syndrome was made. During the parathyroidectomy in May 1999, parathyroid hyperplasia was discovered and total parathyroidectomy with autotransplantation to the left forearm was performed. The patient required two operations for his MEN 1 syndrome, transsphenoidal adenomectomy and distal pancreatectomy. His preoperative evaluation showed high prolactin (PRL) (214 ng mL), insulin-like growth factor (IGF-1) (809 ng mL), growth hormone (GH) (3.2 ng mL), and proinsulin (51.8 pmol L) low testosterone (141 ng dL), follicle-stimulating hormone (FSH) (3.9 mlU mL), and luteinizing hormone (LH) (1.3 mlU mL) and normal cortisol (19.6 g dL), and gastrin (46 pg...
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 delivery systems will become more sophisticated permitting delivery of nutrients, peptides or drugs to specific segments of the lower gastrointestinal tract. For example, high value peptides which have growth-hormone-like activity may be delivered directly to the small intestine instead of being released in the acidic abomasum, preventing degradation and inactivation. Similarly drugs which are sensitive to ruminal fermentation and the acidity of the abomasum may be targeted for the lower gut.
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.
Her adolescence was complicated by short stature. An endocrinologic and metabolic source for her slowed growth was investigated and no abnormalities were found. Interval growth remained adequate. In addition, during her adolescence, she underwent two corrective surgeries for strabismus and had multiple episodes of otitis media.
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...
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.
Animal models (Darko et al., 1995, Pollmacher et al., 1995). The human immunodeficiency virus and other lenti viruses may affect sleep more directly by resetting circadian rhythms, leading to altered sleep patterns and fatigue (Clark et al., 2005). Dysregulation of the growth hormone axis has also been implicated as a possible cause of sleep disturbance, with studies showing differences in the coupling between delta-frequency sleep EEG amplitude and growth hormone secretion in HIV-positive versus HIV-negative subjects, a change that occurs early in the course of the infection (Darko et al., 1998).
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,
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.
Growth hormone CD Crohn's disease, EGF epidermal growth factor, EGF-R epidermal growth factor receptor, GM-CSF granulocyte-macrophage colony-stimulating factor, GM-CSF-R granulocyte-macrophage colony-stimulating factor receptor, hGH-R human growth hormone receptor, IFN interferon, IL interleukin, TNF tumor necrosis factor, UC ulcerative colitis
This approach has also been applied to the discovery of growth hormone secretagogues (GHS). A 3D pharmacophore model was constructed for this purpose from a set of peptides and nonpeptides with known GHS activity by using DistComp.175 The model was used to search against compound databases for novel scaffolds. Synthesis based on the computational results provided GHS actives (precise number undisclosed), one of which was analoged and led to a compound with 1 nM activity (Figure 9). The analog effort was guided by fragment QSAR analysis.
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 .
A coned-down lateral X-ray of the sella turcica showed a 2 cm area of calcification in the hypothalamus. A follow-up contrast-enhanced MRI study showed a 2 cm solid and cystic mass below the floor of the third ventricle without involvement of the pituitary gland. The optic tracts were laterally displaced around this tumor. Visual field testing was normal. Dynamic pituitary testing with GnRH (100 mcg intravenous bolus), thyrotropin-stimulat-ing hormone (500 mcg intravenous bolus), growth-hormone releasing hormone (1 mcg kg), and corticotropin-releasing hormone (1 mcg kg) resulted in normal FSH, LH, thyrotropin, prolactin, growth hormone, ACTH, and cortisol responses.
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.
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,
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,
Case 1 Adolescent with a Prolactinoma Case 2 Acromegaly with Minimal Growth Hormone Elevation A 27-yr-old woman initially presented to the emergency room in 1988 at age 16 with increasing headaches and decreased visual acuity and was found to have a visual field defect. She also had primary amenorrhea. A computed tomography (CT) scan showed a 2 x 3-cm suprasellar mass and she was admitted to the neurosurgery service. She was operated on for what was thought then to be a craniopharyngioma. Her examination at that time showed a modestly obese young girl of normal height with Tanner Stage IV breast and pubic hair development. Preoperative laboratory results that were not available at the time of the surgery showed a serum PRL of 1270 ng mL, a cortisol of 6.6 g dL, a T4 of 4.8 g dL, a growth hormone (GH) of 1.4 ng mL, a luteinizing hormone (LH) of 3.8 mlU mL, and a follicle-stimulating hormone (FSH) of 17.4 mlU mL. Postoperatively, her PRL was 415 ng mL and she was referred to the...
Side-chain recognition is dominant in peptide-receptor complexes. For instance, aromatic residues have a rigid arrangement and large surface area, causing a great deal of potential free energy and a very low entropic cost that results from binding.105 Some side chains within an interface play a more significant role than others in the energetics of binding and determination of the relative orientation of the two proteins. In the human growth hormone receptor complex, eight of the 31 side chains involved in the interface accounted for approximately 85 of the binding energy, providing the genesis of the 'hot spot' theory106 as a basis for inhibitor design and drug discovery. The recognition of the hormone somatostatin by its GPCRs further emphasizes the importance of side chains in peptide recognition, as many of the amide bonds can be reduced,107 the direction of the peptide backbone can be reversed, and even the whole peptide backbone can be replaced by a saccharide with recognition...
But seem to be recognized with increasing frequency because of improved TSH assays. TSHomas can occur at any age and affect women and men equally (1,2). By the time they are discovered, as in this case, 90 of TSHomas are macroadenomas. Approximately 30 of TSHomas are mixed tumors, with the most common situation being cosecretion with either growth hormone or prolactin. There was no evidence for cosecretion of either hormone in this case. The TSH molecules secreted by the tumor may have variable glyco-sylation, giving rise to variations in the biologic activity of the TSH. This may account for the lack of correlation between the level of TSH in the blood and the degree of hyperthyroidism.
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...
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.
22 Wallace, J.D., Cuneo, R.C., Lundberg, P.A. et al. (2000). Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males. Journal of Clinical Endocrinology and Metabolism, 85, 124-33. 44 Ebeling, P.R., Butler, P.C., Eastell, R., Rizza, R.A. and Riggs, B.L. (1991). The nocturnal increase in growth hormone is not the cause of the nocturnal increase in serum osteocalcin. Acta Endocrinologica (Copenhagen), 73, 368-72.
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...
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)
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).
There are laboratory abnormalities, but these are not found in routine testing decreased serum serotonin (5-HT) (4), decreased serum tryptophan (5), increased cerebrospinal fluid substance P (5), increased serum interleukin-8 (6), thyroid hormone and thyroid stimulating hormone that may be low (7), decreased calcium levels (7), and decreased growth hormone secretion (8) (see Chapter 8).
As noted in Chapter 8, FMS patients with low levels of insulin-like growth factor-1 who received daily injections of growth hormone (over nine months) had significant improvements in symptoms when compared to placebo (101). The injections are extremely, prohibitively, expensive.
The secretory fluid volume being small, theoretically an object suspended in this fluid can be dragged in the direction of flow. Gupta and Sheshadri 5 have analysed peristalsis for a sinusoidal waveform. It is assumed that the tips of cilia in the testis form a sinusoidal envelope. If p(x,t) is the pressure at time t at any point (x,o) along the axis of the tube, and u(x, r, t) is the velocity of fluid within the tube at a point x, at
Be suspected if the iris is seen to be tremulous. This strange wobbling movement of the iris used to be seen in the old days after cataract surgery without an implant, but it is now still seen after injuries to the eye and signifies serious damage. Congenital subluxation of the lens is seen as part of Marfan's syndrome (congenital heart disease, tall stature, long fingers, high arched palate). Congenital glaucoma has already been discussed in the chapter on glaucoma it can be inherited in a dominant manner and is the result of persistent embryonic tissue in the angle of the anterior chamber. When the intraocular pressure is raised in early infancy, the eye becomes enlarged, producing buphthalmos ( bull's eye ). This enlargement with raised pressure does not occur in adults.
Growth hormone is involved in the control ofintestinal permeability (Nayer and Rhodes 2004). Preliminary studies of growth hormone (somatropin) in adult patients with CD suggest that it may be beneficial (Slo-nim et al. 2000). Growth hormone is also being evaluated in phase 2 studies in children with CD (who frequently experience growth failure as a complication of CD) (Calenda et al. 2005).
The endocrine system is particularly susceptible to the long-term effects of cancer therapy. In a survey of the patients attending one late-effects clinic, 41 of patients had an endocrinopathy directly attributable to their disease or treatment 6 . This is likely to be an underestimate as it does not take into account the risk of growth hormone (GH) deficiency, which is now recognized to have important implications in adult life. Within the same group, a further 14 were reported to have problems related to fertility 6 . The endocrine system is particularly affected by radiotherapy, which impacts upon the normal function of the hypotha-lamic-pituitary axis, the thyroid, and the gonads. Chemotherapy can have a significant effect upon gonadal function, affecting steroid hormone secretion and reproductive potential.
Hypopituitarism, deficiency of one or more anterior pituitary hormones growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH), and thyroid-stimulating hormone (TSH) , may be present at the diagnosis of cancer as a result of pathology in the sellar or suprasellar region that destroys normal pituitary tissue or disrupts the pituitary stalk, or may be a result of the treatments used, either surgery or irradiation. Deficiencies of the posterior pituitary hormones, antidiuretic hormone, and oxytocin, may occur in the presence of large suprasellar lesions such as a cranio-pharyngioma or germinoma, but are rarely caused by irradiation.
Department of Agriculture, this vast site includes directions to patents, press releases, and newsletters, as well as compilations of articles on specific topics such as bovine growth hormone and bioremedia-tion. The site invites questions from users.
The patient was thought to have probable amiodarone-induced thyroiditis. He was started on prednisone 40 mg d as a single daily dose. One week later, he noted no improvement in his symptoms, and repeat thyroid function tests were unchanged (fT4 2.8 ng dL, T3 277 ng dL). For this reason, Tapazole 40 mg d was added to the regimen. One week later, thyroid function testing was unchanged, with fT4 2.9 ng dL, T3 282 ng dL. The pred-nisone and methimazole were continued. Two weeks later, the patient developed severe shortness of breath and was hospitalized with a diagnosis of congestive heart failure. Three days after admission, he developed a fever to 103 F with shaking chills. A chest X-ray showed a hazy infiltrate in the right lower lung field. Blood cultures were drawn, and subsequently grew Strep. pneumoniae. Broad spectrum antibiotics were started. A complete blood count (CBC), which had been normal on admission, revealed a white blood count (WBC) of 3000 mm3with 10 granulocytes. The...
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.
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 .
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...
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.
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 .
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