Mary Lee Vance, M.D., and Nelly Mauras, M.D.
Growth hormone is produced by the somatotroph cells of the anterior pituitary. Its secretion is stimulated by growth hormone�releasing hormone and inhibited by somatostatin, which are both produced by the hypothalamus. Growth hormone secretion is pulsatile, and the amplitude of the pulses is greatest at night. Twenty-four-hour growth hormone secretion is maximal during puberty and declines gradually thereafter in both women and men. Growth hormone acts by binding to receptors on liver cells and other cells. One growth hormone molecule binds to two receptor molecules on the target cell, initiating a cascade of events that results in the secretion of insulin-like growth factor I, which mediates many of the biologic actions of growth hormone. Some of the extracellular domain of the receptor is released into the serum, and approximately 50 percent of growth hormone in serum is bound to this part of the receptor. Despite its name, growth hormone has other actions in addition to promoting growth in children.
The goals of growth hormone therapy differ somewhat in adults and children. In adults the goals are to restore normal body composition, improve muscle and cardiac function, normalize serum lipid concentrations, and improve the quality of life. In children the goals are to promote linear growth, restore body composition, and improve the quality of life.
Growth hormone has been administered not only to adults of all ages with growth hormone deficiency, but also to adults with catabolic illnesses, such as burn injuries, and to older adults with decreased growth hormone secretion. However, studies in adults without growth hormone deficiency are limited.
Over 90 percent of adults with growth hormone deficiency have overt pituitary disease, which is usually caused by a pituitary adenoma or by surgery or radiation therapy for a pituitary adenoma.1 Among patients with pituitary adenomas, those with a deficiency of one or more other pituitary hormones are also likely to have growth hormone deficiency.
Growth hormone deficiency has been diagnosed primarily on the basis of subnormal growth hormone secretion in response to stimuli. In the United States the Food and Drug Administration (FDA) has approved growth hormone therapy for adults only if there is evidence of hypothalamic or pituitary disease and a subnormal serum growth hormone response to one stimulation test. The FDA has stipulated that the peak serum growth hormone concentration in response to hypoglycemia or another stimulus should be less than 5 �g per liter, if measured by radioimmunoassay, or less than 2.5 �g per liter, if measured by immunoradiometric assay. The Growth Hormone Research Society has recommended that the diagnosis be based on a stimulated serum growth hormone value of less than 3 �g per liter during hypoglycemia, and this value is widely accepted as diagnostic in Europe.2 Measurements of serum insulin-like growth factor I or insulin-like growth factor�binding protein 3, both of which are growth hormone�dependent, are not reliable indicators of growth hormone deficiency in adults.3 Insulin-induced hypoglycemia is the preferred provocative stimulus, because in patients with pituitary disease the response to this stimulus is more likely to be abnormal than are the responses to levodopa, arginine, growth hormone�releasing hormone, glucagon, and clonidine. However, the insulin test is contraindicated in patients with coronary artery disease, generalized debility, or seizure disorders.
There is evidence that growth hormone deficiency in adults is deleterious, increasing the risk of death from cardiovascular disease. In three retrospective studies of 849 patients with varying degrees of hypopituitarism and presumed growth hormone deficiency, the rate of mortality from cardiovascular disease was 1.9, 1.35, and 1.4 times as high as that of age- and sex-matched normal subjects.4,5,6 The rate of mortality from cancer was either half the rate for normal subjects or similar to it.5,6
As compared with age- and sex-matched normal subjects, adults with growth hormone deficiency have increased fat mass, reduced muscle mass and strength, smaller hearts and lower cardiac output, lower bone density, and higher serum lipid concentrations (Table 1). 1,18,19 They also have decreased vitality, energy, and physical mobility; emotional lability; feelings of social isolation; and disturbances in sexual function, despite adequate correction of hormonal deficiencies other than growth hormone deficiency.20,21,22 These symptoms occur both in patients with childhood-onset deficiency and in those with adult-onset deficiency, but they are more severe in the latter group.1 However, not all adults with growth hormone deficiency have these symptoms.
Although the administration of growth hormone to adults with growth hormone deficiency reverses many of the changes listed in Table 1, the ultimate clinical efficacy of growth hormone treatment is not known. In the various treatment studies, the daily dose of growth hormone ranged from 6 to 26 �g per kilogram of body weight. The doses were intended to raise the serum concentrations of insulin-like growth factor I to well within the normal range. However, it is not possible to reproduce the normal daily pulsatile pattern of growth hormone secretion with a single daily injection. It will probably require more than 20 years of growth hormone replacement to know whether the rates of cardiovascular disease, bone fracture, and mortality, as well as the quality of life, are affected substantially.
The salient changes in body composition and serum lipid concentrations that occur in growth hormone�deficient adults treated with growth hormone are summarized in Table 2. There are regional effects on body composition. For example, in one study of adipose mass, treatment for 26 weeks resulted in a 13 percent decrease in subcutaneous fat mass and a 30 percent decrease in intraabdominal fat mass.26 These changes persisted during one year of treatment, with a 22 percent reduction in overall adipose mass and a 61 percent reduction in trunk fat; conversely, lean body mass increased by 3 to 11 percent.29,34 In several studies, exercise capacity increased by 11 to 19 percent, and muscle strength increased by 7 to 19 percent, reaching values similar to those in normal subjects.9,18,19,20,21,22,24,25,26,29,34,35,36 These increases occurred within four months after the initiation of treatment and persisted during treatment periods of up to three years.36 Cardiac function did not change after six months of treatment in one study.16 In another study, however, there was a 26 percent increase in the left ventricular mass index and a 12 percent increase in systolic function, with a return to pretreatment values six months after the discontinuation of growth hormone treatment.37 There are no data on the effect of treatment on cardiovascular-related morbidity or mortality.
In several studies, growth hormone therapy resulted in small increases in fasting serum glucose and insulin concentrations and in glycosylated hemoglobin values, but all these values remained within the normal range.23,25,26,28,30,33 Treatment for five years did not alter oral glucose tolerance or overall insulin sensitivity, but hepatic insulin sensitivity was less than that of normal subjects.38 After six months of treatment, the basal metabolic rate increased by 6 percent in one study23 and by 11 percent in another.39 Other reported metabolic changes have been small increases in serum triiodothyronine concentrations and transient decreases in serum thyroxine concentrations.26 Growth hormone therapy may increase cortisol degradation, and patients receiving glucocorticoid-replacement therapy may therefore need higher doses.
In some studies, quality-of-life measures, including energy level, mood, sensitivity to pain, emotional lability, and physical mobility, as measured by standardized psychological tests, improved with growth hormone therapy.1,21,33 The effects of growth hormone on these measures appear to differ between adults with adult-onset growth hormone deficiency and those with childhood-onset deficiency. The former had significant improvements in scores for social isolation and physical mobility, whereas the latter had no changes in these scores.1 Among 125 adults treated with placebo or growth hormone for 12 months, the growth hormone�treated patients had significant improvements in scores on standard psychological tests of energy, emotional reactions to stress, and social isolation, so that their scores were similar to those of normal subjects.28 A possible explanation for the improvement in energy is that the changes in the metabolic rate and in muscle and fat mass allowed the patients to become more physically active, but a direct effect of growth hormone on the brain cannot be ruled out.
The most common side effects of growth hormone treatment in adults are edema and arthralgia or myalgia (Table 3). These effects are dose-dependent. The daily dose of growth hormone used in these trials ranged from 6 to 26 �g per kilogram, with dose reductions of 25 to 50 percent if side effects developed or if the serum concentration of insulin-like growth factor I increased above normal. In most patients these effects resolved with a reduction in the dose.
Any patient with a pituitary tumor or craniopharyngioma is at risk for a recurrence of the tumor, but there is no evidence that growth hormone�replacement therapy increases this risk. Another concern is the risk of cancer and cardiovascular disease. This concern arises because of the increased prevalence of these diseases in patients with acromegaly, who have high serum growth hormone concentrations for many years. However, there is at present no evidence that growth hormone�replacement therapy affects the risk of cancer or cardiovascular disease.
According to FDA recommendations, the starting dose of growth hormone in adults is 3 to 4 �g per kilogram given once daily by subcutaneous injection, with a maximal daily dose of 25 �g per kilogram for patients up to 35 years of age and 12.5 �g per kilogram for older patients. These recommendations are based on clinical trials in which growth hormone was administered according to body weight. However, the Growth Hormone Research Society consensus conference has recommended a starting dose of 150 to 300 �g per day, regardless of body weight.2 The goal of therapy is to restore the serum concentration of insulin-like growth factor I to the middle of the normal range for persons of the same sex and similar age. Initially, patients should be evaluated at one-to-two-month intervals by means of clinical observation and measurement of serum insulin-like growth factor I, and the dose of growth hormone should be adjusted as needed to maintain the target value for serum insulin-like growth factor I.
In 1996, growth hormone was approved by the FDA for treatment of wasting or cachexia in patients with the acquired immunodeficiency syndrome (AIDS). This approval was based on evidence that growth hormone increased lean body mass and decreased fat mass in patients with AIDS, although no survival benefit was observed. The use of growth hormone has also been studied in small numbers of adults with other catabolic illnesses, including those associated with respiratory failure, burn injuries, recovery from surgery, congestive cardiomyopathy, liver transplantation, and renal failure. No consistent benefit has yet been demonstrated. In a double-blind, placebo-controlled study involving patients in intensive care units with severe systemic illnesses, the administration of high doses of growth hormone was associated with increased mortality.40
Growth hormone has been given to patients with obesity, osteoporosis, muscular dystrophy, and infertility, but with no consistent benefit. The administration of growth hormone to elderly ambulatory patients resulted in changes in body composition similar to those that occur in adults with growth hormone deficiency. However, no statistically significant improvement in muscle strength or exercise tolerance occurred. Short-term administration of growth hormone to increase strength and endurance in athletes is no more effective than training alone. Growth hormone should therefore not be administered to older adults or to athletes.
Growth hormone is produced by the somatotroph cells of the anterior pituitary. Its secretion is stimulated by growth hormone�releasing hormone and inhibited by somatostatin, which are both produced by the hypothalamus. Growth hormone secretion is pulsatile, and the amplitude of the pulses is greatest at night. Twenty-four-hour growth hormone secretion is maximal during puberty and declines gradually thereafter in both women and men. Growth hormone acts by binding to receptors on liver cells and other cells. One growth hormone molecule binds to two receptor molecules on the target cell, initiating a cascade of events that results in the secretion of insulin-like growth factor I, which mediates many of the biologic actions of growth hormone. Some of the extracellular domain of the receptor is released into the serum, and approximately 50 percent of growth hormone in serum is bound to this part of the receptor. Despite its name, growth hormone has other actions in addition to promoting growth in children.
The goals of growth hormone therapy differ somewhat in adults and children. In adults the goals are to restore normal body composition, improve muscle and cardiac function, normalize serum lipid concentrations, and improve the quality of life. In children the goals are to promote linear growth, restore body composition, and improve the quality of life.
Growth Hormone Replacement Therapy in Adults
Growth hormone has been administered not only to adults of all ages with growth hormone deficiency, but also to adults with catabolic illnesses, such as burn injuries, and to older adults with decreased growth hormone secretion. However, studies in adults without growth hormone deficiency are limited.
Causes of Growth Hormone Deficiency in Adults
Over 90 percent of adults with growth hormone deficiency have overt pituitary disease, which is usually caused by a pituitary adenoma or by surgery or radiation therapy for a pituitary adenoma.1 Among patients with pituitary adenomas, those with a deficiency of one or more other pituitary hormones are also likely to have growth hormone deficiency.
Diagnosis of Growth Hormone Deficiency
Growth hormone deficiency has been diagnosed primarily on the basis of subnormal growth hormone secretion in response to stimuli. In the United States the Food and Drug Administration (FDA) has approved growth hormone therapy for adults only if there is evidence of hypothalamic or pituitary disease and a subnormal serum growth hormone response to one stimulation test. The FDA has stipulated that the peak serum growth hormone concentration in response to hypoglycemia or another stimulus should be less than 5 �g per liter, if measured by radioimmunoassay, or less than 2.5 �g per liter, if measured by immunoradiometric assay. The Growth Hormone Research Society has recommended that the diagnosis be based on a stimulated serum growth hormone value of less than 3 �g per liter during hypoglycemia, and this value is widely accepted as diagnostic in Europe.2 Measurements of serum insulin-like growth factor I or insulin-like growth factor�binding protein 3, both of which are growth hormone�dependent, are not reliable indicators of growth hormone deficiency in adults.3 Insulin-induced hypoglycemia is the preferred provocative stimulus, because in patients with pituitary disease the response to this stimulus is more likely to be abnormal than are the responses to levodopa, arginine, growth hormone�releasing hormone, glucagon, and clonidine. However, the insulin test is contraindicated in patients with coronary artery disease, generalized debility, or seizure disorders.
Clinical Manifestations
There is evidence that growth hormone deficiency in adults is deleterious, increasing the risk of death from cardiovascular disease. In three retrospective studies of 849 patients with varying degrees of hypopituitarism and presumed growth hormone deficiency, the rate of mortality from cardiovascular disease was 1.9, 1.35, and 1.4 times as high as that of age- and sex-matched normal subjects.4,5,6 The rate of mortality from cancer was either half the rate for normal subjects or similar to it.5,6
As compared with age- and sex-matched normal subjects, adults with growth hormone deficiency have increased fat mass, reduced muscle mass and strength, smaller hearts and lower cardiac output, lower bone density, and higher serum lipid concentrations (Table 1). 1,18,19 They also have decreased vitality, energy, and physical mobility; emotional lability; feelings of social isolation; and disturbances in sexual function, despite adequate correction of hormonal deficiencies other than growth hormone deficiency.20,21,22 These symptoms occur both in patients with childhood-onset deficiency and in those with adult-onset deficiency, but they are more severe in the latter group.1 However, not all adults with growth hormone deficiency have these symptoms.
Response to Growth Hormone
Although the administration of growth hormone to adults with growth hormone deficiency reverses many of the changes listed in Table 1, the ultimate clinical efficacy of growth hormone treatment is not known. In the various treatment studies, the daily dose of growth hormone ranged from 6 to 26 �g per kilogram of body weight. The doses were intended to raise the serum concentrations of insulin-like growth factor I to well within the normal range. However, it is not possible to reproduce the normal daily pulsatile pattern of growth hormone secretion with a single daily injection. It will probably require more than 20 years of growth hormone replacement to know whether the rates of cardiovascular disease, bone fracture, and mortality, as well as the quality of life, are affected substantially.
The salient changes in body composition and serum lipid concentrations that occur in growth hormone�deficient adults treated with growth hormone are summarized in Table 2. There are regional effects on body composition. For example, in one study of adipose mass, treatment for 26 weeks resulted in a 13 percent decrease in subcutaneous fat mass and a 30 percent decrease in intraabdominal fat mass.26 These changes persisted during one year of treatment, with a 22 percent reduction in overall adipose mass and a 61 percent reduction in trunk fat; conversely, lean body mass increased by 3 to 11 percent.29,34 In several studies, exercise capacity increased by 11 to 19 percent, and muscle strength increased by 7 to 19 percent, reaching values similar to those in normal subjects.9,18,19,20,21,22,24,25,26,29,34,35,36 These increases occurred within four months after the initiation of treatment and persisted during treatment periods of up to three years.36 Cardiac function did not change after six months of treatment in one study.16 In another study, however, there was a 26 percent increase in the left ventricular mass index and a 12 percent increase in systolic function, with a return to pretreatment values six months after the discontinuation of growth hormone treatment.37 There are no data on the effect of treatment on cardiovascular-related morbidity or mortality.
In several studies, growth hormone therapy resulted in small increases in fasting serum glucose and insulin concentrations and in glycosylated hemoglobin values, but all these values remained within the normal range.23,25,26,28,30,33 Treatment for five years did not alter oral glucose tolerance or overall insulin sensitivity, but hepatic insulin sensitivity was less than that of normal subjects.38 After six months of treatment, the basal metabolic rate increased by 6 percent in one study23 and by 11 percent in another.39 Other reported metabolic changes have been small increases in serum triiodothyronine concentrations and transient decreases in serum thyroxine concentrations.26 Growth hormone therapy may increase cortisol degradation, and patients receiving glucocorticoid-replacement therapy may therefore need higher doses.
In some studies, quality-of-life measures, including energy level, mood, sensitivity to pain, emotional lability, and physical mobility, as measured by standardized psychological tests, improved with growth hormone therapy.1,21,33 The effects of growth hormone on these measures appear to differ between adults with adult-onset growth hormone deficiency and those with childhood-onset deficiency. The former had significant improvements in scores for social isolation and physical mobility, whereas the latter had no changes in these scores.1 Among 125 adults treated with placebo or growth hormone for 12 months, the growth hormone�treated patients had significant improvements in scores on standard psychological tests of energy, emotional reactions to stress, and social isolation, so that their scores were similar to those of normal subjects.28 A possible explanation for the improvement in energy is that the changes in the metabolic rate and in muscle and fat mass allowed the patients to become more physically active, but a direct effect of growth hormone on the brain cannot be ruled out.
Side Effects
The most common side effects of growth hormone treatment in adults are edema and arthralgia or myalgia (Table 3). These effects are dose-dependent. The daily dose of growth hormone used in these trials ranged from 6 to 26 �g per kilogram, with dose reductions of 25 to 50 percent if side effects developed or if the serum concentration of insulin-like growth factor I increased above normal. In most patients these effects resolved with a reduction in the dose.
Any patient with a pituitary tumor or craniopharyngioma is at risk for a recurrence of the tumor, but there is no evidence that growth hormone�replacement therapy increases this risk. Another concern is the risk of cancer and cardiovascular disease. This concern arises because of the increased prevalence of these diseases in patients with acromegaly, who have high serum growth hormone concentrations for many years. However, there is at present no evidence that growth hormone�replacement therapy affects the risk of cancer or cardiovascular disease.
Dose of Growth Hormone
According to FDA recommendations, the starting dose of growth hormone in adults is 3 to 4 �g per kilogram given once daily by subcutaneous injection, with a maximal daily dose of 25 �g per kilogram for patients up to 35 years of age and 12.5 �g per kilogram for older patients. These recommendations are based on clinical trials in which growth hormone was administered according to body weight. However, the Growth Hormone Research Society consensus conference has recommended a starting dose of 150 to 300 �g per day, regardless of body weight.2 The goal of therapy is to restore the serum concentration of insulin-like growth factor I to the middle of the normal range for persons of the same sex and similar age. Initially, patients should be evaluated at one-to-two-month intervals by means of clinical observation and measurement of serum insulin-like growth factor I, and the dose of growth hormone should be adjusted as needed to maintain the target value for serum insulin-like growth factor I.
Other Uses of Growth Hormone in Adults
In 1996, growth hormone was approved by the FDA for treatment of wasting or cachexia in patients with the acquired immunodeficiency syndrome (AIDS). This approval was based on evidence that growth hormone increased lean body mass and decreased fat mass in patients with AIDS, although no survival benefit was observed. The use of growth hormone has also been studied in small numbers of adults with other catabolic illnesses, including those associated with respiratory failure, burn injuries, recovery from surgery, congestive cardiomyopathy, liver transplantation, and renal failure. No consistent benefit has yet been demonstrated. In a double-blind, placebo-controlled study involving patients in intensive care units with severe systemic illnesses, the administration of high doses of growth hormone was associated with increased mortality.40
Growth hormone has been given to patients with obesity, osteoporosis, muscular dystrophy, and infertility, but with no consistent benefit. The administration of growth hormone to elderly ambulatory patients resulted in changes in body composition similar to those that occur in adults with growth hormone deficiency. However, no statistically significant improvement in muscle strength or exercise tolerance occurred. Short-term administration of growth hormone to increase strength and endurance in athletes is no more effective than training alone. Growth hormone should therefore not be administered to older adults or to athletes.
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