Growth hormone tests

Definition

Growth hormone tests measure the levels of specific hormones that regulate human growth. These hormone levels are measured in blood serum samples obtained by venipuncture. To study growth hormone function under specific conditions, certain medications may be administered before blood is taken and hormone levels are measured. Human growth hormone (hGH) (somatotropin) is produced by somatotropes in the anterior pituitary gland. Its role in normal body growth and development is to stimulate protein production in muscle cells and trigger energy release from the breakdown of fats. Diagnostic tests for growth hormones include the somatotropin hormone test, somatomedin C test, growth hormone stimulation test (also known as the arginine test or insulin tolerance test), and growth hormone suppression test (glucose loading test).

Purpose

Growth hormone tests are ordered by physicians to determine whether levels of hGH and other related hormones in the blood are normal, increased, or decreased, and to help diagnose conditions that may result from abnormal hormone levels or pituitary gland dysfunction. Some of the common reasons for testing are:

• to identify growth abnormalities that may cause delayed puberty and small stature in adolescents
• to aid in the diagnosis of hyperpituitarism, which can cause gigantism or acromegaly
• to screen for pituitary gland dysfunction
• to assist in the diagnosis of pituitary tumors or tumors related to the hypothalamus, an area of the brain
• to monitor the effects of hGH therapy administered for certain conditions

Description

Human growth hormones play an important role in normal human growth and development. The major human growth hormone is a protein made up of 191 amino acids, the building blocks of proteins. The production of this protein is controlled by two other hormones secreted by the hypothalamus: growth hormone releasing hormone (GHRH), which controls secretion of hGH; and growth hormone-inhibiting hormone (GHIH), which inhibits secretion of hGH. All healthy individuals have measurable levels of hGH throughout life, but there are two notable growth spurts, one at birth and the other at puberty, and hGH plays a vital role at each time. The most obvious effect of hGH is on linear skeletal growth (height), but metabolic effects of hGH (the results of hGH activity in the body) on muscle, the liver, and fat cells are a critical part of its function. When any question arises about growth or development, pediatricians may investigate the levels of the major growth hormone hGH, its receptors and stimulants, the glands that produce the hormones, and the complex hormone interactions that control normal development.

Somatotropin (hGH) is secreted by somatotropes in the anterior pituitary gland. It is typically secreted during sleep , with peak release occurring around 10 p.m., midnight, and 2 a.m. Most of the effects of hGH are mediated by other hormones, including the somatomedins, IGH-I (somatomedin C) and IGH-II, which are insulin-like growth hormones that also influence linear growth, and the two hypothalamic hormones (GHRH and GHIH) that regulate hGH by responding to changes in the individual's blood sugar (glucose) and protein levels. When blood glucose levels fall, GHRH triggers the secretion of stored hGH. As blood glucose levels rise, hGH secretion is turned off by GHIH activity. Increases in blood protein levels trigger a similar response. This feedback loop, along with the effects of eating and exercise , is responsible for the fluctuating levels of hGH throughout the day. In addition, blood glucose and amino acid availability for growth is also regulated by the hormones adrenaline, glucagon, and insulin. All of these growth factors may be evaluated in order to understand hormone deficiencies or gland dysfunction when growth deficiencies are suspected.

A number of hormonal conditions can lead to excessive or diminished growth. Because of its critical role in producing hGH and other hormones, a dysfunctional pituitary gland will often lead to altered growth. Dwarfism (very small stature) can be due to underproduction of hGH, lack of IGH-I, or a flaw in target tissue response to either of these growth hormones. Overproduction of hGH or IGH-I, or an exaggerated response to these hormones, can lead to gigantism or acromegaly, both of which are characterized by a very large stature.

Gigantism is the result of hGH overproduction in early childhood leading to a skeletal height up to 8 feet (2.5 m) or more. Acromegaly results when hGH is over-produced after the onset of puberty. In this condition, the epiphyseal plates of the long bones of the body do not close, and they remain responsive to additional stimulated growth by hGH. This disorder is characterized by an enlarged skull, hands and feet, nose, neck, and tongue.

Somatrotropin

Somatrotropin (hGH) is measured in the clinical laboratory to identify hGH deficiency in adolescents with short stature, delayed sexual maturity, and other growth or development abnormalities. The somatotropin test also aids in documenting the excess hGH production responsible for gigantism or acromegaly, and confirms underactivity or overproduction of the pituitary gland (hypopituitarism or hyperpituitarism, respectively). However, due to variable secretion of hGH, as well as hGH production in response to stress, exercise, or other factors, random assays are not an adequate determination of hGH deficiency. To obtain more accurate readings, a blood sample can be drawn one to one-and-a-half hours after sleep (hGH levels increase during sleep), or strenuous exercise can be performed for 30 minutes before blood is drawn. (A person's hGH levels increase after exercise.) The hGH levels at the end of an exercise period are expected to be maximal.

Somatomedin C

The somatomedin C test is usually ordered to help detect pituitary abnormalities, hGH deficiency, and acromegaly. Also called insulin-like growth factor (IGF-1), somatomedin C is considered a more accurate reflection of the blood concentration of hGH because such variables as time of day, activity levels, or diet do not influence test results. Somatomedin C is part of a group of peptides, called somatomedins, through which hGH exerts its effects. Because it circulates in the bloodstream bound to long-lasting proteins, it is more stable than hGH. Levels of somatomedin C do depend on hGH levels, however, and typically somatomedin C levels will be low when hGH levels are deficient. Abnormally low levels of somatomedin C will require further investigation, so doctors may perform the hGH stimulation test to diagnose hGH deficiency. Nonpituitary causes of reduced somatomedin C include malnutrition , severe chronic illness, severe liver disease, hypothyroidism , and Laron's dwarfism.

Growth hormone stimulation test

The hGH stimulation test, also called hGH provocation test, insulin tolerance, or arginine test, is performed to test the body's ability to produce human growth hormone and to confirm suspected hGH deficiency. A normal patient can have low hGH levels, but if hGH is still low after stimulation, a more definitive diagnosis can be made. The test involves creating a condition of insulin-induced hypoglycemia (via intravenous injection of insulin) to stimulate production of hGH and corticotropin secretion as well. If such stimulation is unsuccessful, a malfunction of the anterior pituitary gland is likely. It may be necessary to obtain blood samples following an energetic exercise session lasting 20 minutes.

A substance called hGH-releasing factor has also been used for hGH stimulation. This approach is believed to be more accurate and specific for hGH deficiency caused by the pituitary. Growth hormone deficiency is also suspected when x-ray determination of bone age indicates retarded growth in comparison to chronological age. As of 2004, the best method to identify hGH-deficient patients was a positive stimulation test followed by a positive response to a therapeutic trial of hGH.

Growth hormone suppression test

This procedure, also called the glucose loading test, is performed to evaluate excessive baseline levels of hGH and to confirm diagnosis of gigantism in children (and acromegaly in adults). The procedure requires drawing two different blood samples, one before the child ingests 100 grams of glucose by mouth and a second sample two hours after glucose ingestion. Normally, a glucose load such as this will suppress hGH secretion. In a child with excessive hGH levels, failure of suppression indicates anterior pituitary dysfunction and confirms a diagnosis of gigantism (or acromegaly).

Precautions

Taking certain drugs such as amphetamines, dopamine, corticosteroids, and phenothiazines may increase or decrease growth hormone secretion. A pediatrician may discontinue certain medications prior to the performance of growth hormone tests. Other factors that may influence hGH secretion include stress, exercise, diet, and abnormal glucose levels. The pediatrician may make recommendations for the child's activity prior to testing. Growth hormone tests should not be done within a week after any radioactive scan such as an x ray, MRI, or CT scan.

Preparation

The hGH or somatotropin test requires that a fasting blood sample be drawn from a vein, usually in the arm. The child should have nothing to eat or drink from midnight the night before the test until after the blood sample is drawn. Since stress and exercise increase hGH levels, the child must be at complete rest for 30 minutes before the blood sample is drawn. If the physician has requested two samples, they should be drawn on consecutive days at approximately the same time, preferably between 6 a.m. and 8 a.m.

The somatomedin C test also requires a fasting blood sample. The patient should have nothing to eat or drink from midnight the night before until after the blood sample is drawn.

Growth hormone stimulation testing requires intravenous administration of arginine and/or insulin. Venous blood samples will be drawn at 0, 60, and 90 minutes after the injection.

Growth hormone suppression testing requires two fasting blood samples, one before the test and another two hours after the child is given a glucose solution by mouth. The child should have nothing to eat or drink from midnight the night before until after the blood samples are drawn, and physical activity should be limited for at least 10 to 12 hours before the test.

Aftercare

Usually there will be no effects from hormone testing and normal activities can be resumed. A bandage may be applied to keep the site of venipuncture or intravenous administration of medications clean and to stop any bleeding that may occur. Unusual bleeding or bruising of the site should be reported to the pediatrician. The child should be observed closely after the more extensive growth hormone stimulation test and growth hormone suppression test. A pediatrician may limit activities for the immediate pre-test period.

Risks

Growth hormone tests do not have significant risks. Minor discomfort may be experienced during and after the growth hormone stimulation test because of the intravenous line for delivery of insulin. A low blood sugar (hypoglycemia) will result from the insulin injected into the child's system, which may make some children light-headed or lethargic. Some children may experience sleepiness, sweating, and/or nervousness, all of which can be corrected after the test by ingestion of juice or a glucose infusion, as recommended by the pediatrician. Severe cases of hypoglycemia may cause ketosis (excessive amounts of fatty acid byproducts in the body), acidosis (a disturbance of the body's acid-base balance), or shock. Medical personnel provide close observation during the test to help prevent or react to these unlikely reactions. Growth hormone suppression tests can cause some children to feel nauseous after the administration of glucose. Ice chips can help alleviate this symptom.

Normal results

Results are reported in nanograms per milliliter (ng/ml). Normal results may vary from laboratory to laboratory depending upon the method used for measurement, but results are usually within the following ranges.

Somatotropin (hGH):

• men: 5 ng/ml
• women: less than 10 ng/ml
• children: 0–10 ng/ml
• newborn: 10–40 ng/ml

Somatomedin C:

• adult: 42–110 ng/ml
• child: 0–8 years; girls 7–110 ng/ml; boys 4–87 ng/ml
• 9–10 years: girls 39–186 ng/ml; boys 26–98 ng/ml
• 11–13 years: girls 66–215 ng/ml; boys 44–207 ng/ml
• 14–16 years: girls 96–256 ng/ml; boys 48–255 ng/ml

Growth hormone stimulation: greater than 10 ng/ml

KEY TERMS

Acromegaly —A rare disease resulting from excessive growth hormone caused by a benign tumor. If such a tumor develops within the first ten years of life, the result is gigantism (in which growth is accelerated) and not acromegaly. Symptoms include coarsening of the facial features, enlargement of the hands, feet, ears, and nose, jutting of the jaw, and a long face.

Dwarfism, pituitary —Short stature. When caused by hGH deficiency, as opposed to late growth spurt or genetics, abnormally slow growth and short stature with normal proportions may be seen.

Gigantism —Excessive growth, especially in height, resulting from overproduction of growth hormone during childhood or adolescence by a pituitary tumor. Untreated, the tumor eventually destroys the pituitary gland, resulting in death during early adulthood. If the tumor develops after growth has stopped, the result is acromegaly, not gigantism.

Pituitary gland —The most important of the endocrine glands (glands that release hormones directly into the bloodstream), the pituitary is located at the base of the brain. Sometimes referred to as the "master gland," it regulates and controls the activities of other endocrine glands and many body processes including growth and reproductive function. Also called the hypophysis.

Regarding growth hormone suppression, normally, glucose suppresses hGH to levels ranging from undetectable to 3 ng/ml within 30 minutes to two hours. In children, rebound stimulation may occur after two to five hours.

Parental concerns

Parents may be concerned about the child's response to venipuncture or reaction to intravenous administration of medications prior to testing. The parents can play a calming role by reassuring the child and explaining the procedure beforehand. Medical personnel and the pediatrician may provide instruction before, during, and after the tests, as well as close observation to minimize any risks. Parents can be prepared for post-testing sleepiness or lightheadedness by having juice handy and ice chips to help relieve any feelings of nausea .

Resources

BOOKS

Czernichow, P., et al. Growth and Metabolic Disorders in Chronic Pediatric Diseases: Cambridge December 2001 Hormone Research. Basel, Switzerland: S. Karger AG, 2002.

DeGroot, Leslie, et al. Hormone Action, Pituitary Growth, and Maturation, Immunology, Nutrition, Diabetes Mellitus. Kent, UK: Elsevier—Health Science Division, 2001.

WEB SITES

"Growth Hormone." Lab Tests Online: American Association for Clinical Chemistry, 2001–2004. Available online at <www.labtestsonline.org/understanding/analytes/growth_hormone/test.html> (accessed October 21, 2004).

L. Lee Culvert Janis O. Flores

Growth Hormone Tests

Definition

Growth hormone (hGH), or somatotropin, is a hormone responsible for normal body growth and development by stimulating protein production in muscle cells and energy release from the breakdown of fats. Tests for growth hormone include Somatotropin hormone test, Somatomedin C, Growth hormone suppression test (glucose loading test), and Growth hormone stimulation test (Arginine test or Insulin tolerance test).

Purpose

Growth hormone tests are ordered for the following reasons:

• to identify growth deficiencies, including delayed puberty and small stature in adolescents that result from pituitary or thyroid malfunction
• to aid in the diagnosis of hyperpituitarism that is evident in gigantism or acromegaly
• to screen for inadequate or reduced pituitary gland function
• to assist in the diagnosis of pituitary tumors or tumors related to the hypothalamus, an area of the brain
• to evaluate hGH therapy

Precautions

Taking certain drugs such as amphetamines, dopamine, corticosteroids, and phenothiazines may increase and decrease growth hormone secretion, respectively. Other factors influencing hGH secretion include stress, exercise, diet, and abnormal glucose levels. These tests should not be done within a week of any radioactive scan.

Description

Several hormones play important roles in human growth. The major human growth hormone (hGH), or somatotropin, is a protein made up of 191 amino acids that is secreted by the anterior pituitary gland and coordinates normal growth and development. Human growth is characterized by two spurts, one at birth and the other at puberty. hGH plays an important role at both of these times. Normal individuals have measurable levels of hGH throughout life. Yet levels of hGH fluctuate during the day and are affected by eating and exercise. Receptors that respond to hGH exist on cells and tissues throughout the body. The most obvious effect of hGH is on linear skeletal development. But the metabolic effects of hGH on muscle, the liver, and fat cells are critical to its function. Surprisingly, a 2004 study reported that obese people have lower-than-normal levels of human growth hormone in their bodies. Humans have two forms of hGH, and the functional difference between the two is unclear. They are both formed from the same gene, but one lacks the amino acids in positions 32-46.

hGH is produced in the anterior portion of the pituitary gland by somatotrophs under the control of hormonal signals in the hypothalamus. Two hypothalamic hormones regulate hGH; they are growth hormone-releasing hormone (GHRH) and growth hormone—inhibiting hormone (GHIH). When blood glucose levels fall, GHRH triggers the secretion of stored hGH. As blood glucose levels rise, GHRH release is turned off. Increases in blood protein levels trigger a similar response. As a result of this hypothalamic feedback loop, hGH levels fluctuate throughout the day. Normal plasma hGH levels average 1-3 ng/ML with peaks as high as 60 ng/ML. In addition, plasma glucose and amino acid availability for growth is also regulated by the hormones adrenaline, glucagon, and insulin.

Most hGH is released at night. Peak spikes of hGH release occur around 10 P.M., midnight, and 2 A.M. The logic behind this night-time release is that most of hGH's effects are controlled by other hormones, including the somatomedins, IGH-I and IGH-II. As a result, the effects of hGH are spread out more evenly during the day.

A number of hormonal conditions can lead to excessive or diminished growth. Because of its critical role in producing hGH and other hormones, an abnormal pituitary gland will often yield altered growth. Dwarfism (very small stature) can be due to underproduction of hGH, lack of IGH-I, or a flaw in target tissue response to either of these growth hormones. Overproduction of hGH or IGH-I, or an exaggerated response to these hormones can lead to gigantism or acromegaly, both of which are characterized by a very large stature.

Gigantism is the result of hGH overproduction in early childhood leading to a skeletal height up to 8 feet (2.5m) or more. Acromegaly results when hGH is overproduced after the onset of puberty. In this condition, the epiphyseal plates of the long bone of the body do not close, and they remain responsive to additional stimulated growth by hGH. This disorder is characterized by an enlarged skull, hands and feet, nose, neck, and tongue.

Somatotropin

Somatotropin is used to identify hGH deficiency in adolescents with short stature, delayed sexual maturity, and other growth deficiencies. It also aids in documenting excess hGH production that is responsible for gigantism or acromegaly, and confirms underactivity or overproduction of the pituitary gland (hypopituitarism or hyperpituitarism). However, due to the episodic secretion of hGH, as well as hGH production in response to stress, exercise, or other factors, random assays are not an adequate determination of hGH deficiency. To negate these variables and obtain more accurate readings, a blood sample can be drawn one to 1.5 hours after sleep (hGH levels increase during sleep), or strenuous exercise can be performed for 30 minutes before blood is drawn (hGH levels increase after exercise). The hGH levels at the end of an exercise period are expected to be maximal.

Somatomedin C

The somatomedin C test is usually ordered to detect pituitary abnormalities, hGH deficiency, and acromegaly. Also called insulin-like growth factor (IGF-1), somatomedin C is considered a more accurate reflection of the blood concentration of hGH because such variables as time of day, activity levels, or diet do not influence the results. Somatomedin C is part of a group of peptides, called somatomedins, through which hGH exerts its effects. Because it circulates in the bloodstream bound to long-lasting proteins, it is more stable than hGH. Levels of somatomedin C depend on hGH levels, however. As a result, somatomedin C levels are low when hGH levels are deficient. Abnormally low test results of somatomedin C require an abnormally reduced or absent hGH during an hGH stimulation test in order to diagnose hGH deficiency. Nonpituitary causes of reduced somatomedin C include malnutrition, severe chronic illness, severe liver disease, hypothyroidism, and Laron's dwarfism.

Growth hormone stimulation test

The hGH stimulation test, also called hGH Provocation test, Insulin Tolerance, or Arginine test, is performed to test the body's ability to produce human growth hormone, and to identify suspected hGH deficiency. A normal patient can have low hGH levels, but if hGH is still low after stimulation, a diagnosis can be more accurately made.

Insulin-induced hypoglycemia (via intravenous injection of insulin) stimulates hGH and corticotropin secretion as well. If such stimulation is unsuccessful, then there is a malfunction of the anterior pituitary gland. Blood samples may be obtained following an energetic exercise session lasting 20 minutes.

A substance called hGH-releasing factor has recently been used for hGH stimulation. This approach promises to be more accurate and specific for hGH deficiency caused by the pituitary. Growth hormone deficiency is also suspected when x ray determination of bone age indicates retarded growth in comparison to chronologic age. At present, the best method to identify hGH-deficient patients is a positive stimulation test followed by a positive response to a therapeutic trial of hGH.

Growth hormone suppression test

Also called the glucose loading test, this procedure is used to evaluate excessive baseline levels of human growth hormone, and to confirm diagnosis of gigantism in children and acromegaly in adults. The procedure requires two different blood samples, one drawn before the administration of 100 g of glucose (by mouth), and a second sample two hours after glucose ingestion.

Normally, a glucose load suppresses hGH secretion. In a patient with excessive hGH levels, failure of suppression indicates anterior pituitary dysfunction and confirms a diagnosis of acromegaly and gigantism.

Preparation

Somatotropin: This test requires a blood sample. The patient should be fasting (nothing to eat or drink from midnight the night before the test). Stress and/or exercise increases hGH levels, so the patient should be at complete rest for 30 minutes before the blood sample is drawn. If the physician has requested two samples, they should be drawn on consecutive days at approximately the same time on both days, preferably between 6 a.m. and 8 a.m.

Somatomedin C: This test requires a blood sample. The patient should have nothing to eat or drink from midnight the night before the test.

Growth hormone stimulation: This test requires intravenous administration of medications and the withdrawal of frequent blood samples, which are obtained at 0, 60, and 90 minutes after injection of arginine and/or insulin. The patient should have nothing to eat or drink after midnight the night before the test.

Growth hormone suppression: This test requires two blood samples, one before the test and another two hours after administration of 100 g of glucose solution by mouth. The patient should have nothing to eat or drink after midnight, and physical activity should be limited for 10-12 hours before the test.

Risks

Growth hormone stimulation: Only minor discomfort is associated with this test, and results from the insertion of the IV line and the low blood sugar (hypoglycemia) induced by the insulin injection. Some patients may experience sleepiness, sweating and/or nervousness, all of which can be corrected after the test by ingestion of cookies, juice, or a glucose infusion. Severe cases of hypoglycemia may cause ketosis (excessive amounts of fatty acid byproducts in the body), acidosis (a disturbance of the body's acid-base balance), or shock. With the close observation required for the test, these are unlikely.

Growth hormone suppression: Some patients experience nausea after the administration of this amount of glucose. Ice chips can alleviate this symptom.

Normal results

Normal results may vary from laboratory to laboratory but are usually within the following ranges:

Somatotropin:

• men: 5 ng/ml
• women: less than 10 ng/ml
• children: 0-10 ng/ml
• newborn: 10-40 ng/ml.

Somatomedin C:

• adult: 42-110 ng/ml
• Child:
• 0-8 years: Girls 7-110 ng/ml; Boys 4-87 ng/ml
• 9-10 years: Girls 39-186 ng/ml; Boys 26-98 ng/ml
• 11-13 years: Girls 66-215 ng/ml; Boys 44-207 ng/ml
• 14-16 years: Girls 96-256 ng/ml; Boys 48 255 ng/ml.

Growth hormone stimulation: greater than 10 ng/ml.

Growth hormone suppression: Normally, glucose suppresses hGH to levels of undetectable to 3 ng/ml in 30 minutes to two hours. In children, rebound stimulation may occur after two to five hours.

Abnormal results

Somatotropin hormone: Excess hGH is responsible for the syndromes of gigantism and acromegaly. Excess secretion is stimulated by anorexia nervosa, stress, hypoglycemia, and exercise. Decreased levels are seen in hGH deficiency, dwarfism, hyperglycemia, failure to thrive, and delayed sexual maturity.

Somatomedin C: Increased levels contribute to the syndromes of gigantism and acromegaly. Stress, major surgery, hypoglycemia, starvation, and exercise stimulate hGH secretion, which in turn stimulates somatomedin C.

Growth hormone stimulation: Decreased levels are seen in pituitary deficiency and hGH deficiency. Diseases of the pituitary can result in failure of the pituitary to secrete hGH and/or all the pituitary hormones. As a result, the hGH stimulation test will fail to stimulate hGH secretion.

KEY TERMS

Acromegaly— A rare disease resulting from excessive growth hormone caused by a benign tumor. If such a tumor develops within the first 10 years of life, the result is gigantism (in which growth is accelerated) and not acromegaly. Symptoms include coarsening of the facial features, enlargement of the hands, feet, ears, and nose, jutting of the jaw, and a long face.

Dwarfism, pituitary— Short stature. When caused by inadequate amounts of growth hormone (as opposed to late growth spurt or genetics), hGH deficiency results in abnormally slow growth and short stature with normal proportions.

Gigantism— Excessive growth, especially in height, resulting from overproduction during childhood or adolescence of growth hormone by a pituitary tumor. Untreated, the tumor eventually destroys the pituitary gland, resulting in death during early adulthood. If the tumor develops after growth has stopped, the result is acromegaly, not gigantism.

Pituitary gland— The pituitary is the most important of the endocrine glands (glands that release hormones directly into the bloodstream). Sometimes referred to as the "master gland," the pituitary regulates and controls the activities of other endocrine glands and many body processes.

Growth hormone suppression: The acromegaly syndrome elevates base hGH levels to 75 ng/ml, which in turn are not suppressed to less than 5 ng/ml during the test. Excess hGH secretion may cause unchanged or rising hGH levels in response to glucose loading, confirming a diagnosis of acromegaly or gigantism. In such cases, verification of results is required by repeating the test after a one-day rest.

Resources

PERIODICALS

"Weight-loss Hormone." Better Nutrition (May 2004): 32.

GROWTH HORMONE

A large body of scientific evidence has accumulated to support the concept that decreases in anabolic hormones that occur with aging contribute to the aging-related decline in tissue function and the aging phenotype. Growth hormone and insulin-like growth factor-1 (IGF-1) are two potent anabolic hormones, and decreases in these hormones have been hypothesized to contribute to the loss of muscle and bone mass, as well as cognitive and immune function, in older adults. In young adults, growth hormone is released in pulsatile bursts from the pituitary gland, with the majority of secretion occurring at night in association with slow-wave sleep. Similar pulses are observed in rodents, except that secretory pulses occur every 3.5 hours in males and hourly in females. The regulation of these pulses involve at least two hormones released by the hypothalamus: first, a growth-hormone-releasing hormone (GHRH), which increases growth-hormone release; and second, somatostatin, which inhibits its release. The dynamic interactions between these hypothalamic hormones regulate high amplitude, pulsatile, growth-hormone secretion. Activation of the hepatic growth-hormone receptor by growth hormone stimulates the synthesis and secretion of IGF-1 into plasma, which, in turn, stimulates DNA, RNA, and protein synthesis and is a potent mitogen for many tissues. Growth hormone and IGF-1 circulating in the blood suppress growth-hormone release from the pituitary in a typical feedback relationship—either directly at the level of the pituitary, or by stimulating somatostatin and/or inhibiting GHRH release from the hypothalamus.

Studies in humans have indicated a substantial decline in the ability of older individuals to secrete growth hormone, and it is now evident that the decline in high-amplitude growth-hormone secretion and plasma IGF-1 concentrations are one of the most robust and well-characterized events that occur with age. Similar to humans, decreases in the amplitude of growth-hormone pulses are observed in rodent models of aging, and these changes, as expected, are closely associated with a decline in plasma IGF-1. Although the specific etiology for the decline in growth-hormone pulse amplitude has not been fully detailed, studies in both humans and animals have documented that, rather than a decline in pituitary response to these hypothalamic peptides, alterations in the secretion of both hypothalamic release and inhibiting hormones appear to be the key factors in the decline in growth-hormone pulse amplitude with age. Since these hypothalamic hormones are controlled by brain neurotransmitters, the concept has evolved that alterations in the regulation of neurotransmitters within the brain are part of the mechanism for the decrease in growth hormone.

Although an attenuation of growth-hormone pulse amplitude is an important contributing factor in the decline in plasma IGF-1, studies have also demonstrated that, in response to growth-hormone administration, the ability to increase IGF-1 secretion is diminished in elderly individuals. These results indicate that not only a decline in growth-hormone pulse amplitude, but also tissue resistance to growth-hormone action, is responsible for the reduced plasma IGF-1 concentrations. In rodents, a two-fold increase in hepatic growth-hormone receptors has been reported with age, but this increase is unable to compensate for the reduced levels of growth hormone. Thus, there appears to be a failure of circulating growth hormone to activate intracellular signaling pathways that, in addition to the decrease in growth hormone, contribute to a decline in blood levels of IGF-1 in both animals and humans.

Even though a decreased response to growth hormone is an important component of the age-related decline in plasma IGF-1, this deficit can be partially overcome by administration of exogenous growth hormone. Studies in rodents have revealed that the administration of growth hormone increases IGF-1 and restores cellular protein synthesis in the muscle of old animals, indicating that the age-related decline in tissue function results, at least in part, from hormone deficiency. Other reports have been published demonstrating that either growth hormone or IGF-1 could partially reverse the decline in immune function, increase blood vessel elasticity, and increase life span in rodents. These studies were the first indications that the decrease in the concentration of growth hormone has clinical significance and may be responsible for the generalized catabolic state that accompanies normal aging. In the elderly, it has generally been reported that growth-hormone administration increases IGF-1, lean body mass, muscle mass, and skin thickness, and also reduces total body-fat content. In addition, there are reports of elevations in serum osteocalcin (a marker of bone formation) and nitrogen retention, raising the possibility that growth-hormone treatment may delay osteoporosis.

In addition to its role in regulating tissue growth, more recent studies indicate that administration of growth hormone reverses the age-related loss of blood vessels. These and related studies indicating that IGF-1 is produced in microvessels have led to the concept that a reduction in growth hormone and the subsequent decrease in plasma and microvascular-derived IGF-1 lead to a decline in tissue function and/or reduce the capacity of tissues to respond to appropriate stimuli. In fact, raising levels of IGF-1 in old animals has been shown to improve the function of several neurotransmitter systems, glucose utilization and cognition, and also to improve contractility in the heart.

Although there are many potential beneficial effects of growth-hormone therapy in aged animals and humans, the adverse effects of therapy include sodium retention, carpal tunnel syndrome, potential glucose resistance, and hyperinsulinemia. Epidemiological studies also indicate a significant correlation between levels of IGF-1 and prostate, breast, and lung cancer, raising the concern that administration of these mitogenic hormones may initiate and/or accelerate pathological changes in the elderly. These issues have not been directly tested to date, but studies indicate that moderate caloric restriction (60 percent of ad libitum food intake), which is capable of decreasing age-related pathology, also lowers plasma IGF-1 levels. Subsequent administration of IGF-1 to these animals removes the protective effects of moderate caloric restriction from specific carcinogens, providing support for the concept that the beneficial effects of moderate caloric restriction are mediated, in part, by decreasing levels of IGF-1. The association between IGF-1 and age-associated pathogenesis remains to be established. Thus, the available evidence suggests that a decline in growth hormone and IGF-1 contribute to the functional decline in tissues with age, but that raising the levels of these hormones may increase the risk of age-related pathology.

William E. Sonntag

See also Biomarkers of Aging; Endocrine System; Neuroendocrine System; Nutrition, Caloric Restriction; Theories of Biological Aging.

BIBLIOGRAPHY

Corpas, E.; Harman, S. M.; and Blackman, M. R. "Human Growth Hormone and Human Aging." Endocrine Review 14 (1993): 20–39.

Rudman, D.; Feller, A. G.; Nagraj, H. S.; Gergans, G. A.; Lalitha, P. Y.; Goldberg, A. F.; Schlenker, R. A.; Cohn, L.; Rudman, I. W.; and Mattson, D. E. "Effects of Human Growth Hormone in Men over 60 Years Old." New England Journal of Medicine 323 (1990): 1–6.

Sonntag, W. E.; Lynch, C. D.; Cefalu, W. T.; Ingram, R. L.; Bennett, S. A.; Thornton, P. L.; and Khan, A. S. "Pleiotropic Effects of Growth Hormone and Insulin-Like Growth Factor (IGF)-1 on Biological Aging: Inferences from Moderate Caloric-Restricted Animals." Journal of Gerontology; Biological Sciences 54A (1999): 521–538.

Xu, X., and Sonntag, W. E. "Growth Hormone and Aging: Regulation, Signal Transduction and Therapeutic Intervention." Trends in Endocrinology and Metabolism 7 (1996): 145–150.

growth hormone also called somatotrophin, is secreted from the anterior part of the pituitary gland. It is a major product of the gland, which contains 5 mg of the hormone (about 10% of its dry weight). As the name implies, growth hormone is important in controlling linear growth and, together with the thyroid hormones and the sex hormones, is important in determining the final height and development of an individual. It also has a role in controlling metabolism of foodstuffs, so that lack of the hormone in children results in short stature with the whole body in proportion, whereas deficiency in the adult results in weakness and depression.

Growth stops when the epiphyses (ends) of the bones fuse to the main shaft between them. Oversecretion before this occurs results in gigantism, whereas oversecretion afterwards results in acromegaly, a condition characterized by coarsening of the facial features and enlargement of the hands and feet. Interest in dwarfism, gigantism, and acromegaly has spanned the centuries; literature, especially for children, is filled with stories about dwarfs and giants, while Old Testament writings have several descriptions of giants. A study of paintings can also reveal subjects with disturbances of growth hormone secretion. A portrait from about 1365 bc of Tutankhamun's father-in-law illustrates some of the chacterisitics of acromegaly, but it was not until the late eighteenth century that Saucerette, a French surgeon, described a subject with features suggestive of this condition. During the nineteenth century a number of reports appeared and the term ‘acromegaly’ was coined in 1886 by Pierre Marie. In the following year, Minkowski (who also performed some of the early experiments important in the discovery of insulin) noted that acromegaly was associated with a pituitary tumour. Such tumours are now known to be the cause of gigantism and acromegaly. Once this was established, surgical treatment of the condition began to be attempted in the 1890s. In 1912 Cushing, a famous American neurosurgeon who also made major contributions to endocrinology, pioneered the technique of operating on pituitary tumours via the nasal route.

The nasal approach to the pituitary is possible because the gland itself lies in the midline at the base of the brain. Part of the visual pathway, the ‘optic chiasma’, lies in front of the pituitary, so a spreading tumour may lead to visual defects. This could explain why Goliath of Gath failed to see the pebble launched by David.

Growth hormone is a large peptide of 191 amino acids and is relatively species-specific, so only primate growth hormone is effective in man. This meant that until 1985, when it became possible to synthesize it, treatment of short stature employed growth hormone extracted from human pituitaries. As with some preparations of human gonadotrophins previously used in fertility treatment, some of the preparations were contaminated, leading to 1 in 1000 patients developing Creuzfeld Jacob disease, resulting in dementia and death. Currently biosynthetic growth hormone is employed.

Growth hormone is always detectable in the plasma of healthy individuals throughout life; it is not secreted continuously over the 24 hours, but in bursts. The most marked increase follows the onset of sleep, so there may be a basis for the old wives' tale that you will not grow if you do not get a good night's sleep. The hormone is present in the fetus, but does not appear to be necessary for growth until soon after birth. Its release is increased in puberty, at an earlier stage in girls than in boys. Secretion of growth hormone is controlled by the hypothalamus, a region of the brain which is important in regulating many functions including a major role in the response to stress: growth hormone is released in response to a number of stresses such as exercise, anaesthesia, and surgery. Prolonged stress may however suppress growth hormone release, so that children with marked emotional deprivation can show secondary growth failure. One such case is said to be Sir James Barrie who was short of stature and may have had some affinity with his creation, Peter Pan.

Release is stimulated in response to a rapid fall in blood glucose, which can be produced by an injection of insulin in a clinical test for growth hormone secretion. The hypothalamus controls growth hormone secretion by means of its own secretion of two peptides; somatostatin, which inhibits secretion, and growth hormone releasing hormone, which is stimulatory; these hormones reach the nearby anterior pituitary through local blood vessels.

Growth hormone stimulates the growth of the long bones, not directly but through the action of somatomedins, which are insulin-like growth factors made in the liver, and which also inhibit release of the hormone. It has a direct effect on metabolic processes throughout the body, supporting growth through enhanced formation of protein and nucleic acids (anabolic action) and of other constituents of lean body mass. By contrast its effects promote breakdown of carbohydrate and fat, with the energy released supporting growth. Because of the anabolic effects and because detection is difficult, growth hormone has been used by athletes to improve performance, although studies have shown it to be of little value.

Mary L. Forsling

Growth Hormone

Human growth hormone (HGH) stimulates the growth of bones and affects the metabolism of carbohydrate , protein , and fat . It is secreted by the pituitary gland , which is located in the brain. Whereas HGH is produced in the body, genetic engineering has resulted in the development of recombinant human growth hormone (rHGH), which is used to treat stunted growth in children. Bovine somatotropin (BST) is a naturally occurring protein hormone in cows that increases milk production when administered as a supplement. BST is not biologically active in humans and is broken down into inactive amino acids and peptides when consumed. Therefore, milk from cows treated with BST is believed to be as safe and nutritious as milk from untreated cows.

Supplemental HGH is used by athletes, particularly body builders and power lifters, to increase muscle mass and decrease body fat. Individuals who are HGH-deficient and take supplemental HGH will see an increase in muscle mass and decreased body fat, whereas those with normal HGH levels will see an increase in lean body mass from an increase in the size of heart, liver, and kidneys, and from fluid retention, but there will be no increase in muscle mass. Excessive use can cause acromegaly (an increase in the size of the bones of the hand, feet, and jaw), as well as muscle weakness, arthritis , impotence, and diabetes . Since HGH increases the size of the liver, kidneys, and heart, its use can predispose the individual to chronic diseases. HGH is classified as an anabolic hormone, and its ability to increase muscle and decrease fat confers an unfair athletic advantage on the user. The use of HGH is thus banned by the International Olympic Committee (IOC), the National Collegiate Athletic Association (NCAA), and many professional sporting organizations.

see also Ergogenic Acids; Sports Nutrition.

Leslie Bonci

Bibliography

Rosenbloom, Christine, ed. (2000). Sports Nutrition: A Guide for the Professional Working with Active People, 3rd edition. Chicago: American Dietetic Association.

Williams, M. (1998). The Ergogenics Edge. Champaign, IL: Human Kinetics.