Human Growth Hormone
The first step in our education is to become familiar with some of the terms and definitions used while discussing Human Growth Hormone. Ready? Let's jump right in...
What is a Hormone?
Hormones are tiny chemical messengers that help our body do different tasks. Hormones are made up of amino acids. Hormones are produced by the endocrine glands and then sent all over the body to stimulate certain activities. For example, Insulin is a well known hormone that helps our body digest food. Our growth, digestion, reproduction and sexual functions are all triggered by hormones.
What is Human Growth Hormone?
Growth Hormone (HGH) is the most abundant hormone
produced by the pituitary gland (pituitary is one of the
endocrine glands). The pituitary gland is located in the
center of the brain. HGH is also a very complex hormone.
It is made up of 191 amino acids making it fairly large
for a hormone. In fact, it is the largest protein
created by the Pituitary gland.
What is Recombinant Growth Hormone (GH)?
Recombinant Growth Hormone is GH that is synthesized in the lab. It is a biosynthetic hormone that is identical to human growth hormone, but it is synthesized in the lab. Creating an exact replicate of HGH was not an easy task.
What is IGF-1?
IGF-1 stands for Insulin-like Growth Factor 1. IGF-1 is also known as Somatomedin-C. As important as HGH is, it does not last long in our bloodstream. In just a few short minutes our liver absorbs HGH and converts it into growth factors. IGF-1 is the most important growth factor that is produced. So, IGF-1 is a hormone just like HGH, but it is easier to measure in the body because it stays in our bloodstream longer than HGH. You can think of HGH as the hormone that gets the ball rolling, but IGF-1 does most of the work.
What is a Secretagogue?
A secretagogue (se-krët´ah-gog) is an agent that stimulates secretion. For now that is all you need to know about these agents with a funny name, but as we move on the functions of secretagogues and HGH enhancement will become important.
Physiologic Effects of Growth Hormone
A critical concept in understanding growth hormone activity is that it has two distinct types of effects:
Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and suppresses their ability to take up and accumulate circulating lipids.
Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.
Effects on Growth
Growth is a very complex process, and requires the
coordinated action of several hormones. The major role
of growth hormone in stimulating body growth is to
stimulate the liver and other tissues to secrete IGF-I.
IGF-I stimulates proliferation of chondrocytes
(cartilage cells), resulting in bone growth. Growth
hormone does seem to have a direct effect on bone growth
in stimulating differentiation of chondrocytes.
Control of Growth Hormone Secretion
Production of growth hormone is modulated by many factors, including stress, exercise, nutrition, sleep and growth hormone itself. However, its primary controllers are two hypothalamic hormones and one hormone from the stomach:
Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone.
Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. Somatostatin inhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration.
Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates secretion of growth hormone.
Growth hormone secretion is also part of a negative feedback loop involving IGF-I. High blood levels of IGF-I lead to decreased secretion of growth hormone not only by directly suppressing the somatotroph, but by stimulating release of somatostatin from the hypothalamus.
Growth hormone also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph.
Integration of all the factors that affect growth hormone synthesis and secretion lead to a pulsatile pattern of release. Basal concentrations of growth hormone in blood are very low. In children and young adults, the most intense period of growth hormone release is shortly after the onset of deep sleep.
Growth hormone deficiency
Growth Hormone Deficiency (GHD) is a medical condition in which the body does not produce enough growth hormone (GH). Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction. HGH also refers to human growth hormone but this older abbreviation has begun to develop paradoxical connotations, particularly in relation to the peddling of medically unnecessary GH supplementation (so-called HGH quackery).
Growth hormone deficiency has
different effects at different ages. In newborn infants
the primary manifestations may be hypoglycemia or
micropenis, while in later infancy and childhood, growth
failure is more likely. Deficiency in adults is rare,
but may feature diminished lean body mass, poor bone
density, and a number of physical and psychological
symptoms. Psychological symptoms include poor memory,
social withdrawal, and depression, while physical
symptoms may include loss of strength, stamina, and
musculature. Other hormonal or glandular disorders
frequently coincide with diminished growth hormone
GH deficiency can be congenital or acquired in childhood or adult life. It can be partial or complete. It is usually permanent, but sometimes transient. It may be an isolated deficiency or occur in association with deficiencies of other pituitary hormones.
The term hypopituitarism is often used interchangeably with GH deficiency by endocrinologists but more often denotes GH deficiency plus deficiency of at least one other anterior pituitary hormone. When GH deficiency (usually with other anterior pituitary deficiencies) is associated with posterior pituitary hormone deficiency (usually diabetes insipidus) the condition is termed panhypopituitarism.
Signs and symptoms
The incidence of idiopathic GHD in infants is about 1 in every 3800 live births, and rates in older children are rising as more children survive childhood cancers which are treated with radiotherapy, although exact rates are hard to obtain. Severe prenatal deficiency of GH, as occurs in congenital hypopituitarism, has little effect on fetal growth. However, prenatal and congenital deficiency can reduce the size of a male's penis, especially when gonadotropins are also deficient. Besides micropenis, additional consequences of severe deficiency in the first days of life can include hypoglycemia and exaggerated jaundice (both direct and indirect hyperbilirubinemia). Female infants will lack the microphallus of course but may suffer from hypoglycemia and jaundice.
Even congenital GH deficiency does not usually impair length growth until after the first few months of life. From late in the first year until mid teens, poor growth and/or shortness is the hallmark of childhood GH deficiency. Growth is not as severely affected in GH deficiency as in untreated hypothyroidism, but growth at about half the usual velocity for age is typical. It tends to be accompanied by delayed physical maturation so that bone maturation and puberty may be several years delayed. When severe GH deficiency is present from birth and never treated, adult heights can be as short as 48-58 inches (122-147 cm).
Severe GH deficiency in early childhood also results in slower muscular development, so that gross motor milestones such as standing, walking, and jumping may be delayed. Body composition (i.e., the relative amounts of bone, muscle, and fat) is affected in many children with severe deficiency, so that mild to moderate chubbiness is common (though GH deficiency alone rarely causes severe obesity). Some severely GH-deficient children have recognizable, cherubic facial features characterized by maxillary hypoplasia and forehead prominence (said to resemble a kewpie doll).
Children have sparse hair growth and frontal recession, and pili torti and trichorrhexis nodosa are also sometimes present.
The incidence of genuine adult-onset GHD, normally due to pituitary tumours, is estimated at 10 per million.
Recognised effects include:
· Increased 5-alpha-reductase
· Reduced sex hormone binding globulin (SHBG)
· Reduced muscle mass and strength
· Baldness in men
· Reduced bone mass and osteoporosis
· Reduced quality of life, particularly energy levels
· Impaired concentration and loss of memory
· Increased body fat, particularly around the waistline
· Lipid abnormalities, particularly raised LDL cholesterol
· Insulin resistance
· Increased levels of fibrinogen and plasminogen activator inhibitor
· Cardiac dysfunction, including a thickened intima media
Childhood GHD commonly has no identifiable cause (idiopathic), and adult-onset GHD is commonly due to pituitary tumours and their treatment or to cranial irradiation. A fuller list of causes includes:
· mutations of specific genes (e.g., GHRHR, GH1)
· congenital diseases such as Prader-Willi syndrome, Turner syndrome, or short stature homeobox-containing gene (SHOX) deficiency
· congenital malformations involving the pituitary (e.g., septo-optic dysplasia, posterior pituitary ectopia)
· chronic renal insufficiency
· some infants who are small for gestational age
· intracranial tumors in or near the sella turcica, especially craniopharyngioma
· damage to the pituitary from radiation therapy to the head (e.g. for leukemia or brain tumors), from surgery, from trauma, or from intracranial disease (e.g. hydrocephalus)
· autoimmune inflammation (hypophysitis)
· ischemic or hemorrhagic infarction from low blood pressure (Sheehan syndrome) or hemorrhage pituitary apoplexy
There are a variety of rare diseases which resemble GH deficiency, including the childhood growth failure, facial appearance, delayed bone age, and low IGF levels. However, GH testing elicits normal or high levels of GH in the blood, demonstrating that the problem is not due to a deficiency of GH but rather to a reduced sensitivity to its action. Insensitivity to GH is traditionally termed Laron dwarfism, but over the last 15 years many different types of GH resistance have been identified, primarily involving mutations of the GH binding protein or receptors.
As an adult ages, it is normal for the pituitary to produce diminishing amounts of GH and many other hormones, particularly the sex steroids. Physicians therefore distinguish between the natural reduction in GH levels which comes with age, and the much lower levels of "true" deficiency. Such deficiency almost always has an identifiable cause, with adult-onset GHD without a definable cause ("idiopathic GH deficiency") extremely rare. GH does function in adulthood to maintain muscle and bone mass and strength, and has poorly-understood effects on cognition and mood.
Pediatric endocrinologists are the physicians who specialize in diagnosis and treatment of growth hormone deficiency and growth problems in children. Internist endocrinologists are the physicians with the most expertise in assessment and treatment of adult GH deficiency. Although GH can be readily measured in a blood sample, testing for GH deficiency is constrained by the fact that levels are nearly undetectable for most of the day. This makes simple measurement of GH in a single blood sample useless for detecting deficiency. Physicians therefore use a combination of indirect and direct criteria in assessing GHD, including:
· Auxologic criteria (defined by body measurements)
· Indirect hormonal criteria (IGF levels from a single blood sample)
· Direct hormonal criteria (measurement of GH in multiple blood samples to determine secretory patterns or responses to provocative testing), in particular:
· Subnormal frequency and amplitude of GH secretory peaks when sampled over several hours
· Subnormal GH secretion in response to at least two provocative stimuli
· Increased IGF1 levels after a few days of GH treatment
· Response to GH treatment
· Corroborative evidence of pituitary dysfunction
"Provocative tests" involve giving a dose of an agent that will normally provoke a pituitary to release a burst of growth hormone. An intravenous line is established, the agent is given, and small amounts of blood are drawn at 15 minute intervals over the next hour to determine if a rise of GH was provoked. Agents which have been used clinically to stimulate and assess GH secretion are arginine, levodopa, clonidine, epinephrine and propranolol, glucagon and insulin. An insulin tolerance test has been shown to be reproducible, age-independent, and able to distinguish between GHD and normal adults, and so is the test of choice.
Severe GH deficiency in childhood additionally has the following measurable characteristics:
· Proportional stature well below that expected for family heights, although this characteristic may not be present in the case of familial-linked GH deficiency
· Below-normal velocity of growth
· Delayed physical maturation
· Delayed bone age
· Low levels of IGF1, IGF2, IGF binding protein 3
· Increased growth velocity after a few months of GH treatment
In childhood and adulthood, the diagnosing doctor will look for these features accompanied by corroboratory evidence of hypopituitarism such as deficiency of other pituitary hormones, a structurally abnormal pituitary, or a history of damage to the pituitary. This would confirm the diagnosis; in the absence of pituitary pathology, further testing would be required.
Growth hormone treatment
GH deficiency is treated by replacing GH with daily injections under the skin or into muscle. Until 1985, growth hormone for treatment was obtained by extraction from human pituitary glands collected at autopsy. Since 1985, recombinant human growth hormone (rhGH) is a recombinant form of human GH produced by genetically engineered bacteria, manufactured by recombinant DNA technology. In both children and adults, costs of treatment in terms of money, effort, and the impact on day-to-day life, are substantial.
Treatment in childhood
GH treatment is not recommended for children who are not growing despite having normal levels of growth hormone, and in the UK it is not licensed for this use. Children requiring treatment usually receive daily injections of growth hormone. Most pediatric endocrinologists monitor growth and adjust dose every 3–6 months and many of these visits involve blood tests and x-rays. Treatment is usually extended as long as the child is growing, and lifelong continuation may be recommended for those most severely deficient. Nearly painless insulin syringes, pen injectors, or a needle-free delivery system reduce the discomfort. Injection sites include the biceps, thigh, buttocks, and stomach. Injection sites should be rotated daily to avoid lipoatrophy. Treatment is expensive, costing as much as $US 10,000 to 40,000 a year in the USA.
Treatment in adulthood
GH supplementation is not recommended medically for the physiologic age-related decline in GH/IGF secretion. It may be appropriate in diagnosed adult-onset deficiency, where a weekly dose approximately 25% of that given to children is given. Lower doses again are called for in the elderly to reduce the incidence of side effects and maintain age-dependent normal levels of IGF-I. In many countries, including the UK, the majority view among endocrinologists is that the failure of treatment to provide any demonstrable, measurable benefits in terms of outcomes means treatment is not recommended for all adults with severe GHD, and national guidelines in the UK as set out by NICE suggest three criteria which all need to be met for treatment to be indicated:
1. Severe GH deficiency, defined as a peak GH response of <9mU/litre during an insulin tolerance test
2. Perceived impairment of quality of life, as assessed by questionnaire
3. They are already treated for other pituitary hormone disorders
· Joint pain and muscle pain
· Fluid retention, and carpal tunnel syndrome
· Mild hypertension
· Visual problems
· Nausea and vomiting
· Antibody formation
· Reactions at the injection site
· Rarely, benign intracranial hypertension.
When treated with GH, a severely deficient child will begin to grow faster within months. In the first year of treatment, the rate of growth may increase from half as fast as other children are growing to twice as fast (e.g., from 1 inch a year to 4 inches, or 2.5 cm to 10). Growth typically slows in subsequent years, but usually remains above normal so that over several years a child who had fallen far behind in his height may grow into the normal height range. Excess adipose tissue may be reduced.
GH treatment can confer a number of measurable benefits to severely GH-deficient adults, such as enhanced energy and strength, and improved bone density. Muscle mass may increase at the expense of adipose tissue. Although adults with hypopituitarism have been shown to have a reduced life expectancy, and a cardiovascular mortality rate more than double controls, treatment has not been shown to improve mortality, although blood lipid levels do improve. Similarly, although measurements of bone density improve with treatment, no rates of fractures have not been shown to improve. Effects on quality of life are unproven, with a number of studies finding that adults with GHD had near-normal indicators of QoL at baseline (giving little scope for improvement), and many using outdated dosing strategies. However, it may be that those adults with poor QoL at the start of treatment do benefi].
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838-1883), who was exhibited by P.T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple appear to show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunk are proportional.
One of the most known persons to have suffered from this deficiency is F.C. Barcelona striker Lionel Messi. He was diagnosed with the disease at the age of eleven and his family couldn't afford its treatment, but that cost was covered by Barcelona in exchange for Messi joining the team's youth departments. Like many other 19th century medical terms which lost precise meaning as they gained wider currency, "midget" as a term for someone with severe proportional shortness acquired pejorative connotations and is no longer used in a medical context.
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