CHAPTER 1
INTRODUCTION

1.1 Structure and gene of the human growth hormone (GH) molecule
The genes for human growth hormone are localized in the q22-24 region of chromosome 17 (GH1) and are closely related to human chorionic somatomammotropin (hCS, also known as placental lactogen) genes. GH, human chorionic somatomammotropin (hCS), and prolactin (PRL) are a group of homologous hormones with growth-promoting and lactogenic activity.
The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of about 22,000 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. GH is structurally and apparently evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and primate growth hormones have significant effects in humans 1
1.2 Secretion of GH
Several molecular forms of GH circulate in our body. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency. The hypothalamic hormones are referred to as releasing hormones and inhibiting hormones, reflecting their influence on anterior pituitary hormones2.

1.3 Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.
1.3.1 Regulators of Release
• Age-Dependence:
Growth hormone levels are highest during puberty. Accordingly, this is when we are growing the most rapidly. After about 30 years of age our growth hormone levels begin to decline at a rate of about 14% per decade.
• Sleep-Dependence:
After an hour, or so, of initiating sleep we enter into a mode of deep sleep known as Slow Wave Sleep, or SWS. SWS occur only during the initial hours of sleep and appear to be inhibited as the night progresses. Growth hormone is principally released from the anterior pituitary during moments of SWS. Therefore, anything that interferes with our SWS will likewise interfere with the release of growth hormone. Alcohol, in particular, interrupts SWS and consequently will also inhibit the release of growth hormone from the anterior pituitary.
• Exercise-Dependence:
Growth hormone is also released following exercise. This aspect of growth hormone release is extremely important for muscle recovery following exercise.

1.4. Other Releasers:
Growth hormone is also released in response to these other physiological stimuli:
• Fasting
• Low blood sugar
• Stress
• Injury or Trauma
• Fever
• Dopaminergic Agonists (Neurotransmitters)
1.5 Central nervous system release
The Hypothalamus is a part of the brain that serves to integrate and respond to information it receives from the rest of the body. In particular, the hypothalamus exerts control over the secretions of the Anterior Pituitary, a small gland located at the base of our brains. The pituitary is also important for this mechanism. Therefore, the hypothalamus, via its direct control over the anterior pituitary, indirectly governs the body’s growth and metabolic processes.
Rather than a steady stream, however, growth hormone is released from the anterior pituitary in spurts due to the competing actions of stimulatory and inhibitory factors originating from the hypothalamus.
1.6. Hypothalamic Factors
Stimulatory: Growth Hormone Releasing Hormone, or GHRH, produced by the hypothalamus mainly stimulates the anterior pituitary to secrete growth hormone.

Inhibitory: Growth hormone inhibitory hormone (GHIH) or Somatostatin antagonizes the release of growth hormone from the anterior pituitary. Like GHRH, somatostatin is produced in the hypothalamus from where it acts on the anterior pituitary.
1.7. Regulatory Feedback
Growth hormone is not wasted. Once secreted into the blood stream growth hormone inhibits its further release from the anterior pituitary (and hypothalamus). The net result is that growth hormone release is favored when its levels are low and is inhibited when it is present in adequate amounts. This is a negative feedback and this prevents the overproduction of growth hormone.
1.8 Effects of Growth Hormone
1.8.1 Direct Effects
Growth Hormone Receptors: Growth hormone directly activates cells expressing growth hormone receptors on their surface. These receptors bind growth hormone after being released from the Anterior Pituitary into the blood stream. The binding of growth hormone to the receptor activates the cell.
Fat Reserves: Fat cells (adipocytes) express high levels of growth hormone receptor. The binding of growth hormone to these receptors causes the adipocyte to release lipids into the blood stream and simultaneously prevents them from taking up lipids from the exterior. In other words, growth hormone mobilizes fats for energy usage. The ultimate result is that our fat reserves get reduced when growth hormone levels are high in circulation.
Growth hormone also slows the use of glucose for energy metabolism
1.9.2. Indirect Effects: (Insulin-like Growth Factor-1)
The majority of growth hormone’s actions, however, are indirect. Most of them are mediated by Insulin-like Growth Factor 1, or IGF-1. IGF-1 is produced by the liver when stimulated by growth hormone; liver cells (hepatocytes) also express high levels of growth hormone receptor. Therefore, increases in growth hormone are commonly mirrored by increased IGF-1. When the growth hormone receptor isn’t functioning properly, however, IGF-1 levels are low relative to growth hormone.
• Muscle Growth: IGF-1 causes muscle cells (myocytes) to increase protein synthesis, reduce protein breakdown, and take up amino acids and to proliferate. In other words, our muscles grow when stimulated by IGF-1.3An athlete or bodybuilder who abuses growth hormone in an attempt to gain muscle size and strength is likely to use other drugs to speed up their physical transformation. The dangers of mixing these drugs aren’t fully known. Some of the drugs used may include:
• Steroids – synthetic versions of the male sex hormone testosterone that build muscle tissue and aid rapid recovery.
• Amphetamines – to aid in fat loss.
• Beta-blockers – to counteract trembling, a common side effect of steroids.
• Diuretics – to counteract fluid retention.
• Bone Growth: Bone cells (chondrocytes) also respond to IGF-1 by proliferating; our bones grow. Connective tissue and cartilage also increase in response to IGF-1.
• Kidneys: Our kidneys and internal organs increase in size in response to IGF-1.

1.10 Regulatory Feedback:
Growth hormone eventually shuts off its own release through a process of regulatory feedback. IGF-1 also feedbacks upon the hypothalamus and anterior pituitary to inhibit further growth hormone release. More precisely, IGF-1 promotes the release of somatostatin from the hypothalamus, as well as directly inhibits growth hormone release from the anterior pituitary.
CHAPTER 2
GROWTH HORMONE TREATMENT
2.1 Who needs to take human growth hormone?
Synthetic human growth hormone is available only by prescription and is administered through an intramuscular injection. It’s currently approved to treat adults with true growth hormone deficiency — not the expected decline in growth hormone due to aging. Growth hormone deficiency can be caused by pituitary tumors and radiation or surgery to the pituitary gland, among other causes3.Human growth hormone is also approved for:
• Children with short stature
• Children with kidney failure
• Children with Prader-Willi syndrome
• Children with Turner’s syndrome
• Muscle wasting associated with AIDS and HIV
Studies of adults with growth hormone deficiencies show that injections of human growth hormone can:
• Increase bone density
• Increase muscle mass
• Decrease body fat
• Bolster the heart’s ability to contract
• Improve mood and motivation
• Increase exercise capacity
Because of those results, people believe that synthetic human growth hormone can help healthy older adults who have naturally low levels of growth hormone regain some of their youth and vitality.
2.2 Assessment of growth hormone secretion
Growth hormone deficiency is a miserable at the world now and it is necessary to identify growth hormone retarded persons among human population. Normally plasma GH level is vary variable, but usually 4it is less than 2mU/l (it may be up to 50 with stress).In order to assess pituitary function and growth hormone secretion following tests4 can be used.
• Post- exercise
• 1 hour after going to sleep Physiological
• frequent sampling during sleep
• Insulin – induced hypoglycaemia
• Clonidine Pharmacological
• Arginine
• Glucagon
2.3 Growth Hormone Disorders
There are numerous conditions associated with alterations of growth hormone production or receptor recognition.

2.4 Growth Hormone Deficiency
2.4.1. Childhood–Dwarfism:
Dwarfism results if the liver and other target tissues are not sufficiently stimulated by growth hormone. This condition arises because either too little growth hormone is produced during childhood, or because the growth hormone receptors expressed by cells are non-functional. Under conditions where the growth hormone receptor isn’t functioning properly, IGF-1 levels are low in comparison to growth hormone.
Mental retardation is also commonly observed in cases of growth hormone deficiency (GHD). Other symptoms of GHD resemble the normal aging process.
2.4.2. Adulthood–Growth Hormone Deficiency (GHD):
Adult onset GHD is characterized by reduced lean body mass, bone density and strength, while visceral fat and mortality, principally due to cardiovascular disease, increases. A characteristic elevation in plasma cholesterol (high LDL/low HDL) is most likely responsible for the increased incidence of cardiovascular disease in GHD patients. Insulin resistance is also frequently encountered. This condition frequently results from the medical intervention of a Pituitary tumor with resultant loss of the growth hormone producing cells, or Somatotropes.
2.4.3. Adulthood–Normal Aging:
This increase in body fat is in large part due to an age dependent decrease in growth hormone. The reduction in growth hormone with age is associated with increased body fat, and reduced muscle mass and bone density. This is a clinical condition referred to as Somatopause. Other aspects of the normal aging process that is correlated with a reduction of growth hormone are cardiovascular disease, wrinkling, gray hair, decreased energy, and reduced sexual function. Many of these same symptoms are present in younger adults with GHD.
2.4.5. Hyper Growth Hormone or Overabundance
Too much growth hormone can have different effects depending on the age at which it occurs. Alarmingly, reduced life expectancy is frequently encountered in natural disorders where growth hormone levels are abnormally elevated.
• Childhood-Giagantism: An overabundance of growth hormone during childhood or adolescence gives rise to giagantism. It is a very rare condition that usually results from a tumor of the cells that produce growth hormone.
• Adulthood–Acromegaly: Acromegaly results from an excess of growth hormone (or IGF-1) during adulthood. IGF-1 is responsible for longitudinal growth (increase in height) during childhood and adolescence. However, an excess of IGF-1 during adult life (after our bones have stopped elongating) causes bones to widen and increase in girth. This disfigures our features, particularly in the face (large square jaw), hands and feet. Glucose intolerance is also commonly observed in acromegliacs. In fact, about one quarter of all acromegliacs develop diabetes mellitus due to peripheral resistance to insulin
2.5 Replacement Therapy
This is a field that is still in its infancy. Previously, human growth hormone was isolated directly from the anterior pituitary of cadavers. This approach yielded extremely small amounts of painfully expensive growth hormone. With the recent advent of genetic engineering, recombinant growth hormone can now be produced more economically in bacteria. Although this has reduced the cost considerably, it is still expensive.
2.6 Uses in Growth Hormone Deficiency (GHD)
Children: GHD in children is most noticeably characterized by stunted growth. Recombinant growth hormone is often used in children with GHD to augment growth.
Adults: Increases in bone density and lean body mass are often observed in patients with adult-onset GHD when treated with recombinant growth hormone. Plasma cholesterol has also been observed to stabilize (lower Low density Lipo protein/higher High DL).

CHAPTER 3
GROWTH HORMONE: USES AND ABUSES
The therapeutic use of human growth hormone was first shown 45 years ago5. In these years the number of approved and proposed uses of human growth hormone has grown and the number of patients being treated with it has increased from a handful to tens of thousands worldwide. The officially approved uses of human growth hormone vary from country to country, but it is commonly used for children with growth hormone deficiency or insufficiency, poor growth due to renal failure, Turner syndrome (girls with a missing or defective X chromosome), Prader-Willi syndrome (usually due to uniparental disomy in chromosome 15), and children born small for gestational age with poor growth 2 years of age. In adults the approved uses include AIDS related wasting and growth hormone deficiency (usually due to a pituitary tumour). The evidence supporting these uses of human growth hormone comes from double blind controlled studies, clinical observations, and systematic meta-analyses. In addition to the generally accepted therapeutic uses of human growth hormone, many proposed uses have not been established. Human growth hormone is undisputedly a potent hormone with a wide variety of biological effects. The anabolic actions of human growth hormone have made it attractive as a potential agent for catabolic problems in a wide range of clinical conditions, including severely catabolic patients in an intensive care environment, burns, cystic fibrosis, inflammatory bowel disease, fertility problems, osteoporosis, and Down’s syndrome, and also for people wishing to reverse the effects of ageing and promote athletic prowess. These last two potential uses have received the most attention as abuse of growth hormone.
The definitions of the word abuse include “improper or excessive use.” The classic forms of “abuse” of human growth hormone are athletes or bodybuilders who use it as a way to gain an unfair advantage over their competitors. No good evidence exists that human growth hormone actually works in this setting. The lay bodybuilding literature is full of testimonials, but as human growth hormone is as least as potent as an anabolic agent no doubt is left that growth hormone should be banned in sport. The use of human growth hormone in sport is promoted by the fact that as yet no practical method exists to detect that is in use in competition at the Olympic level. The use of human growth hormone to increase the height of children who are already of normal height should also be considered abuse. Another common form of use of human growth hormone outside the established indication is in its alleged action of reversing or slowing the effects of ageing. The quest for a “fountain of youth” is an age old dream; advertisements in print media and on the internet promote the use of human growth hormone or agents touted as increasing human growth hormone levels. Many of these agents are not growth hormone and do not lead to a sustained increase in concentrations of growth hormone. Although anabolic effects and changes in body composition have clearly been associated with the use of human growth hormone, in elderly people little or no evidence exists of an important positive functional effect on the processes of ageing.
In addition to the lack of evidence for effectiveness of human growth hormone in these proposed uses, it causes side effects such as diabetes, carpal tunnel syndrome, fluid retention, joint and muscle pain, and high blood pressure. Many of these side effects were seen in studies that used much higher doses of human growth hormone than are now used in elderly people, so there is hope that studies using lower doses alone or in combination with modest doses of anabolic steroids may show a positive ratio of benefits to side effects. Well controlled clinical studies are needed to explore the potential uses of human growth hormone in elderly people and of its other potential uses as an anabolic agent. Innate to the use of growth hormone for athletic enhancement6 or age reversal is the idea that if some growth hormone is good, more must be better.7The belief that taking higher doses or more frequent injections of growth hormone can speed up or enhance its supposed beneficial effects can be a risky one. By increasing the amount of growth hormone taken, one may significantly increase the chance of serious side effects. While it may be some years before it is possible to accurately assess the dangers of growth hormone abuse, one need only consider the condition of acromegaly, where levels of growth hormone are elevated for many years, to see the detrimental effects on the body of prolonged excess growth hormone. Serious abnormalities of the heart, skeletal system, and nervous system are seen in these patients along with an increase in heart disease and tumors
3.1 Pharmaceutical and Biotechnological Uses of Growth Hormone
In years past, growth hormone purified from human cadaver pituitaries was used to treat children with severe growth retardation. More recently, the virtually unlimited supply of growth hormone produced using recombinant DNA technology has lead to several other applications to human and animal populations. Human growth hormone is commonly used to treat children of pathologically short stature. There is concern that this practice will be extended to treatment of essentially normal children – so called “enhancement therapy” or growth hormone on demand. Similarly, growth hormone has been used by some to enhance athletic performance. Although growth hormone therapy is generally safe, it is not as safe as any therapy and does entail unpredictable health risks. Parents that request growth hormone therapy for children of essentially-normal stature are clearly misguided. A number of proposed therapeutic uses exploit the anabolic effects of growth hormone in, for example, severely catabolic patients – the evidence for these is limited. Most obvious of these is use by athletes to gain unfair advantage over competitors, although there is no evidence that this works.8The role of growth hormone in normal aging remains poorly understood, but some of the cosmetic symptoms of aging appear to be amenable to growth hormone therapy. This is an active area of research, and additional information and recommendations about risks and benefits will undoubtedly surface in the near future.
Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle. There is no doubt that administration of bovine somatotropin to lactating cow results in increased milk yield, and, depending on the way the cow are managed, can be an economically-viable therapy. However, this treatment engenders abundant controversy, even among dairy farmers. One thing that appears clear is that drinking milk from cattle treated with bovine growth hormone does not pose a risk to human health. Another application of growth hormone in animal agriculture is treatment of growing pigs with porcine growth hormone. Such treatment has been demonstrated to significantly stimulate muscle growth and reduce deposition of fat.
3.2 Research Findings
1. Jovanna Dahlgren and colleagues at Gothenburg University in Sweden analyzed data from 415 short pre-pubertal children who had undergone GH treatment to develop a model that predicts an individual’s response. The team gathered data including the children’s length and weight at birth, height before and during treatment and their parents’ height. The model was then validated by applying it to a group of 112 different children. The model’s accuracy was substantially improved by including data on blood levels of growth hormone and other growth-related hormones, such as insulin-like growth factors and leptin. The models presented serve as a practical clinical tool for selecting children for successful growth hormone treatment, and provide the highest prediction accuracy available. Growth hormone treatments are expensive, involve daily injections, and are associated with the risk of overdose. To assess whether growth hormone treatment would be appropriate for a particular child, an accurate prediction of how much growth would result from the treatment is crucial.9 This new research will help clinicians determine the children most likely to benefit from treatment, and the most appropriate dose.
2. Towards the Development of a Test for Growth Hormone Abuse – A Study of Extreme Physiological Ranges of Growth Hormone Dependent Markers in 813 Elite Athletes in the Post-Competition Setting.
10Study has demonstrated that there are predictable age dependent levels of GH-dependent markers in elite athletes that are consistent even at the extremes of physical exertion and that these are independent of sporting category. Normative data applicable to white athletes is provided. This provides important groundwork for the development of a test for GH abuse, although these values may be specific for the reagents and assays used.
3. Growth hormone abuse- 11 Doping with growth hormone (GH) has become an increasing problem in sports during the last 10 years. GH has a reputation of being fairly effective among GH users, although the effectiveness is not undisputed, and the few controlled studies that have been performed with supraphysiological GH doses to athletes have shown no significant positive effects of GH in the aspect of a doping agent. There is no method yet to discover GH doping, but current intensive research in this matter will hopefully produce a method in the years to come. This article describes the GH physiology, the clinical use of GH, the athlete’s view, administration regimens and side effects.

REFERENCES
1. http//www. wikipedia.org/ wiki/growth_hormone html
2. www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/anatomy.html
3. http://www.mayoclinic.org/ Human_growth_hormone htm
4. Davidson s., Edward C.R.W., Bouchier I.A.D, 1996. Davidson’s Principle and practice of medicine 17th edition, Great Britain. Pg 675,1152
5. http://www.pubmed.com/ Growth hormone: uses and abuses html (Raymond L Hintz,)
6. Martin M. Zdanowicz, 1997. Human Growth Hormone: Ethical and Economic Considerations of Use and Misuse, Boston (review article)
7. http// dsonline\dsarticles.nsf\pages\health_conditions\ Hormonal system\general htm
8. http://www.ukmicentral.nhs.uk/headline/database/story.asp?NewsID=3165
9. http://www.sciencedaily.com/releases/2007/12/071212201410.htm
10. http://jcem.endojournals.org/cgi/content/abstract/jc.2004-0386v1
11. http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=10932811&cmd=showdetailview&indexed (Ehrnborg C, Bengtsson BA, Rosén T.)

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