Growth hormone, also known as somatotropin, is a
protein hormone of about 190 amino acids that is synthesized and secreted
by cells called somatotrophs in the anterior pituitary. It is a
major participant in control of several complex physiologic processes,
including growth and metabolism. Growth hormone is also of considerable
interest as a drug used in both humans and animals.
Structure and gene of the human GH molecule
The genes for human growth hormone are localized in the
q22-24 region of chromosome 17 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
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.
Secretion of GH
GH is secreted into the blood by the somatotrope cells of
the anterior pituitary gland, in larger amounts than any other pituitary
hormone. 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.
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. Growth hormone
releasing hormone (GHRH) from the arcuate nucleus and ghrelin promote GH
secretion, and somatostatin from the periventricular nucleus inhibits it.
GH secretion is also affected by negative feedback from circulating
concentrations of GH and IGF-1.
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. Stimulators of
GH secretion include (among others) sleep, exercise, hypoglycemia, dietary
protein, and estradiol. Inhibitors of GH secretion include dietary
carbohydrate and glucocorticoids.
Most of the physiologically important GH secretion occurs
as several large pulses or peaks of GH release each day. The plasma
concentration of GH during these peaks may range from 5 to 30 ng/mL or
more. Peaks typically last from 10 to 30 minutes before returning to basal
levels. The largest and most predictable of these GH peaks occurs about an
hour after onset of sleep. Otherwise there is wide variation between days
and individuals. Between the peaks, basal GH levels are low, usually less
than 3 ng/mL for most of the day and night.
The amount and pattern of GH secretion change throughout
life. Basal levels are highest in early childhood. The amplitude and
frequency of peaks is greatest during the pubertal growth spurt. Healthy
children and adolescents average about 8 peaks per 24 hours. Adults
average about 5 peaks. Basal levels and the frequency and amplitude of
peaks decline throughout adult life.
Several molecular forms of GH circulate. 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
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 supresses 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.
Keeping this distinction in mind, we can discuss two major
roles of growth hormone and its minion IGF-I in physiology.
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.
IGF-I also appears to be the key player in muscle
growth. It stimulates both the differentiation and proliferation of
myoblasts. It also stimulates amino acid uptake and protein synthesis in
muscle and other tissues. Metabolic
Growth hormone has important effects on protein, lipid and
carbohydrate metabolism. In some cases, a direct effect of growth hormone
has been clearly demonstrated, in others, IGF-I is thought to be the
critical mediator, and some cases it appears that both direct and indirect
effects are at play.
- Protein metabolism: In general, growth hormone
stimulates protein anabolism in many tissues. This effect reflects
increased amino acid uptake, increased protein synthesis and decreased
oxidation of proteins.
- Fat metabolism: Growth hormone enhances the
utilization of fat by stimulating triglyceride breakdown and oxidation
- Carbohydrate metabolism: Growth hormone is one
of a battery of hormones that serves to maintain blood glucose within a
normal range. Growth hormone is often said to have anti-insulin
activity, because it supresses the abilities of insulin to stimulate
uptake of glucose in peripheral tissues and enhance glucose synthesis in
the liver. Somewhat paradoxically, administration of growth hormone
stimulates insulin secretion, leading to hyperinsulinemia.
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
- 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
- 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
Growth hormone also feeds back to inhibit GHRH secretion
and probably has a direct (autocrine) inhibitory effect on secretion from
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.
States of both growth hormone deficiency and excess
provide very visible testaments to the role of this hormone in normal
physiology. Such disorders can reflect lesions in either the
hypothalamus, the pituitary or in target cells. A deficiency state can
result not only from a deficiency in production of the hormone, but in the
target cell's response to the hormone.
Clinically, deficiency in growth hormone or receptor
defects are as growth retardation or dwarfism. The manifestation of
growth hormone deficiency depends upon the age of onset of the disorder
and can result from either heritable or acquired disease.
The effect of excessive secretion of growth hormone is
also very dependent on the age of onset and is seen as two distinctive
- Giantism is the result of excessive growth
hormone secretion that begins in young children or adolescents. It is a
very rare disorder, usually resulting from a tumor of somatotropes. One
of the most famous giants was a man named Robert Wadlow. He weighed 8.5
pounds at birth, but by 5 years of age was 105 pounds and 5 feet 4
inches tall. Robert reached an adult weight of 490 pounds and 8 feet 11
inches in height. He died at age 22.
- Acromegaly results from excessive secretion of
growth hormone in adults. The onset of this disorder is typically
insideous. Clinically, an overgrowth of bone and connective tissue leads
to a change in appearance that might be described as having "coarse
features". The excessive growth hormone and IGF-I also lead to metabolic
derangements, including glucose intolerance.
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 recombinant growth
hormone has lead to several other applications to human and animal
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 atheletic performance. Although
growth hormone therapy is generally safe, it is not as safe as no therapy
and does entail unpredictable health risks. Parents that request growth
hormone therapy for children of essentially-normal stature are clearly
The 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 cows results in
increased milk yield, and, depending on the way the cows 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