The long arm of human chromosome 17 contains the growth hormone-hCS cluster that contains five genes: one, hGH-N, codes for the most abundant (“normal”) form of growth hormone; a second, hGH-V, codes for the variant form of growth hormone (see below); two code for human chorionic somatomammotropin (hCS) (see Chapter 22); and the fifth is probably an hCS pseudogene.
Growth hormone that is secreted into the circulation by the pituitary gland consists of a complex mixture of hGH-N, peptides derived from this molecule with varying degrees of posttranslational modifications, such as glycosylation, and a splice variant of hGH-N that lacks amino acids 32–46. The physiologic significance of this complex array of hormones has yet to be fully understood, particularly since their structural similarities make it difficult to assay for each species separately. Nevertheless, there is emerging evidence that, while the various peptides share a broad range of functions, they may occasionally exert actions in opposition to one another. hGH-V and hCS, on the other hand, are primarily products of the placenta, and as a consequence are only found in appreciable quantities in the circulation during pregnancy (see Chapter 22).
The structure of growth hormone varies considerably from one species to another. Porcine and simian growth hormones have only a transient effect in the guinea pig. In monkeys and humans, bovine and porcine growth hormones do not even have a transient effect on growth, although monkey and human growth hormones are fully active in both monkeys and humans. These facts are relevant to public health discussions surrounding the presence of bovine growth hormones (used to increase milk production) in dairy products, as well as the popularity of growth hormone supplements, marketed via the Internet, with body builders. Controversially, recombinant human growth hormone has also been given to children who are short in stature, but otherwise healthy (ie, without growth hormone deficiency), with apparently limited results.
PLASMA LEVELS, BINDING, & METABOLISM
A portion of circulating growth hormone is bound to a plasma protein that is a large fragment of the extracellular domain of the growth hormone receptor (see below). It appears to be produced by cleavage of receptors in humans, and its concentration is an index of the number of growth hormone receptors in the tissues. Approximately 50% of the circulating pool of growth hormone activity is in the bound form, providing a reservoir of the hormone to compensate for the wide fluctuations that occur in secretion (see below).
The basal plasma growth hormone level measured by radioimmunoassay in adult humans is normally less than 3 ng/mL. This represents both the protein-bound and free forms. Growth hormone is metabolized rapidly, at least in part in the liver. The half-life of circulating growth hormone in humans is 6–20 min, and the daily growth hormone output has been calculated to be 0.2–1.0 mg/d in adults.
The growth hormone receptor is a 620-amino-acid protein with a large extracellular portion, a transmembrane domain, and a large cytoplasmic portion. It is a member of the cytokine receptor superfamily, which is discussed in Chapter 3. Growth hormone has two domains that can bind to its receptor, and when it binds to one receptor, the second binding site attracts another, producing a homodimer (Figure 18–3). Dimerization is essential for receptor activation.
Some of the principal signaling pathways activated by the dimerized growth hormone receptor (GHR). Solid arrows indicate established pathways; dashed arrows indicate probable pathways. The details of the PLC pathway and the pathway from Grb2 to MAP K are discussed in Chapter 2. The small uppercase letter Ps in yellow hexagons represent phosphorylation of the factor indicated. GLE-1 and GLE-2, interferon γ-activated response elements; IRS, insulin receptor substrate; p90RSK, an S6 kinase; PLA2, phospholipase A2; SIE, Sis-induced element; SRE, serum response element; SRF, serum response factor; TCF, ternary complex factor.
Growth hormone has widespread effects in the body (see below), so even though it is not yet possible precisely to correlate intracellular and whole body effects, it is not surprising that, like insulin, growth hormone activates many different intracellular signaling cascades (Figure 18–3). Of particular note is its activation of the JAK2–STAT pathway. JAK2 is a member of the Janus family of cytoplasmic tyrosine kinases. STATs (for signal transducers and activators of transcription) are a family of cytoplasmic transcription factors that, upon phosphorylation by JAK kinases, migrate to the nucleus where they activate various genes. JAK–STAT pathways are known also to mediate the effects of prolactin and various other growth factors.
In young animals in which the epiphyses have not yet fused to the long bones (see Chapter 21), growth is inhibited by hypophysectomy and stimulated by growth hormone. Chondrogenesis is accelerated, and as the cartilaginous epiphysial plates widen, they lay down more bone matrix at the ends of long bones. In this way, stature is increased. Prolonged treatment of animals with growth hormone leads to gigantism.
When the epiphyses are closed, linear growth is no longer possible. In this case, an overabundance of growth hormone produces the pattern of bone and soft tissue deformities known in humans as acromegaly. The sizes of most of the viscera are increased. The protein content of the body is increased, and the fat content is decreased (Clinical Box 18–1).
EFFECTS ON PROTEIN & ELECTROLYTE HOMEOSTASIS
Growth hormone is a protein anabolic hormone and produces a positive nitrogen and phosphorus balance, a rise in plasma phosphorus, and a fall in blood urea nitrogen and amino acid levels. In adults with growth hormone deficiency, recombinant human growth hormone produces an increase in lean body mass and a decrease in body fat, along with an increase in metabolic rate and a fall in plasma cholesterol. Gastrointestinal absorption of Ca2+ is increased. Na+ and K+ excretion is reduced by an action independent of the adrenal glands, probably because these electrolytes are diverted from the kidneys to the growing tissues. On the other hand, excretion of the amino acid 4-hydroxyproline is increased during this growth, reflective of the ability of growth hormone to stimulate the synthesis of soluble collagen.
EFFECTS ON CARBOHYDRATE & FAT METABOLISM
The actions of growth hormone on carbohydrate metabolism are discussed in Chapter 24. At least some forms of growth hormone are diabetogenic because they increase hepatic glucose output and exert an anti-insulin effect in muscle. Growth hormone is also ketogenic and increases circulating free fatty acid (FFA) levels. The increase in plasma FFA, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. Growth hormone does not stimulate β cells of the pancreas directly, but it increases the ability of the pancreas to respond to insulinogenic stimuli such as arginine and glucose. This is an additional way growth hormone promotes growth, since insulin has a protein anabolic effect (see Chapter 24).
The effects of growth hormone on growth, cartilage, and protein metabolism depend on an interaction between growth hormone and somatomedins, which are polypeptide growth factors secreted by the liver and other tissues. The first of these factors isolated was called sulfation factor because it stimulated the incorporation of sulfate into cartilage. However, it also stimulated collagen formation, and its name was changed to somatomedin. It then became clear that there are a variety of different somatomedins and that they are members of an increasingly large family of growth factors that affect many different tissues and organs.
The principal (and in humans probably the only) circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedin C) and IGF-II. These factors are closely related to insulin, except that their C chains are not separated (Figure 18–4) and they have an extension of the A chain called the D domain. The hormone relaxin (see Chapter 22) is also a member of this family. Humans have two related relaxin isoforms, and both resemble IGF-II. In humans a variant form of IGF-I lacking three amino terminal amino acid residues has been found in the brain, and there are several variant forms of human IGF-II (Figure 18–4). The mRNAs for IGF-I and IGF-II are found in the liver, in cartilage, and in many other tissues, indicating that they are likely synthesized in these tissues.
Structure of human IGF-I, IGF-II, and insulin (ins) (top). The lower panel shows the structure of human IGF-II with its disulfide bonds, as well as three variant structures: a 21-aa extension of the C-terminus, a tetrapeptide substitution at Ser-29, and a tripeptide substitution of Ser-33.
CLINICAL BOX 18–1 Gigantism & Acromegaly
Tumors of the somatotropes of the anterior pituitary (pituitary adenomas) secrete large amounts of growth hormone, leading to gigantism in children and to acromegaly in adults. If the tumor arises before puberty, the individual may grow to an extraordinary height. After linear growth is no longer possible, on the other hand, the characteristic features of acromegaly arise, including greatly enlarged hands and feet, vertebral changes attributable to osteoarthritis, soft tissue swelling, hirsutism, and protrusion of the brow and jaw. Abnormal growth of internal organs may eventually impair their function such that the condition, which has an insidious onset, can prove fatal if left untreated. Hypersecretion of growth hormone is accompanied by hypersecretion of prolactin in 20–40% of patients with acromegaly. About 25% of patients have abnormal glucose tolerance tests, and 4% develop lactation in the absence of pregnancy. Acromegaly can be caused by extra-pituitary as well as intrapituitary growth hormone–secreting tumors and by hypothalamic tumors that secrete GHRH, but the latter are rare. THERAPEUTIC HIGHLIGHTS
The mainstay of therapy for acromegaly remains the use of somatostatin analogues that inhibit the secretion of growth hormone. A growth hormone receptor antagonist has become available and has been found to reduce plasma IGF-I and produce clinical improvement in cases of acromegaly that do not respond to other treatments. Surgical removal of the pituitary tumor is also helpful in both acromegaly and gigantism, but sometimes challenging to perform due to the tumor’s often invasive nature. In any case, adjuvant pharmacologic therapy must often be continued after surgery to control ongoing symptoms.
The properties of insulin, IGF-I, and IGF-II are compared in Table 18–2. Both IGF-I and IGF-II are tightly bound to proteins in the plasma and, at least for IGF-I, this prolongs their half-life in the circulation. Six different IGF-binding proteins, with different patterns of distribution in various tissues, have been identified. All are present in plasma, with IGF-binding protein-3 (IGFBP-3) accounting for 95% of the binding in the circulation. The contribution of the IGFs to the insulin-like activity in blood is discussed in Chapter 24. The IGF-I receptor is very similar to the insulin receptor and probably uses similar or identical intracellular signaling pathways. The IGF-II receptor has a distinct structure (see Figure 24–5) and is involved in the intracellular targeting of acid hydrolases and other proteins to intracellular organelles. Secretion of IGF-I is independent of growth hormone before birth but is stimulated by growth hormone after birth, and it has pronounced growth-stimulating activity. Its concentration in plasma rises during childhood and peaks at the time of puberty, then declines to low levels in old age. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. In human fetuses in which it is overexpressed, several organs, especially the tongue, other muscles, kidneys, heart, and liver, develop out of proportion to the rest of the body. In adults, the gene for IGF-II is expressed only in the choroid plexus and meninges.
TABLE 18–2Comparison of insulin and the insulin-like growth factors (IGFs). ||Download (.pdf) TABLE 18–2 Comparison of insulin and the insulin-like growth factors (IGFs).
| ||Insulin ||IGF-I ||IGF-II |
|Other names ||— ||Somatomedin C ||Multiplication-stimulating activity (MSA) |
|Number of amino acids ||51 ||70 ||67 |
|Source ||Pancreatic β cells ||Liver and other tissues ||Diverse tissues |
|Level regulated by ||Glucose ||Growth hormone after birth, nutritional status ||Unknown |
|Plasma levels ||0.3–2 ng/mL ||10–700 ng/mL; peaks at puberty ||300–800 ng/mL |
|Plasma-binding proteins ||No ||Yes ||Yes |
|Major physiologic role ||Control of metabolism ||Skeletal and cartilage growth ||Growth during fetal development |
Direct and indirect actions of growth hormone (GH). The latter are mediated by the ability of GH to induce production of IGF-I. (Used with permission of R Clark and N Gesundheit.)
DIRECT & INDIRECT ACTIONS OF GROWTH HORMONE
The understanding of the mechanism of action of growth hormone has evolved. It was originally thought to produce growth by a direct action on tissues, and then later was believed to act solely through its ability to induce somatomedins. However, if growth hormone is injected into one proximal tibial epiphysis, a unilateral increase in cartilage width is produced, and cartilage, like other tissues, makes IGF-I. A current hypothesis to explain these results holds that growth hormone acts on cartilage to convert stem cells into cells that respond to IGF-I. Locally produced as well as circulating IGF-I then makes the cartilage grow. However, the independent role of circulating IGF-I remains important, since infusion of IGF-I in hypophysectomized rats restores bone and body growth. Overall, it seems that growth hormone and somatomedins can act both in cooperation and independently to stimulate pathways that lead to growth. The situation is almost certainly complicated further by the existence of multiple forms of growth hormone in the circulation that can, in some situations, have opposing actions.
Figure 18–5 is a summary of current views of the other actions of growth hormone and IGF-I. However, growth hormone probably combines with circulating and locally produced IGF-I in various proportions to produce at least some of the latter effects.
HYPOTHALAMIC & PERIPHERAL CONTROL OF GROWTH HORMONE SECRETION
The secretion of growth hormone is not stable over time. Adolescents have the highest circulating levels of growth hormone, followed by children and finally adults. Levels decline in old age, and there has been considerable interest in injecting growth hormone to counterbalance the effects of aging. The hormone increases lean body mass and decreases body fat, but it does not produce statistically significant increases in muscle strength or mental status. There are also diurnal variations in growth hormone secretion superimposed on these developmental stages. Growth hormone is found at relatively low levels during the day, unless specific triggers for its release are present (see below). During sleep, on the other hand, large pulsatile bursts of growth hormone secretion occur. Therefore, it is not surprising that the secretion of growth hormone is under hypothalamic control. The hypothalamus controls growth hormone production by secreting growth hormone–releasing hormone (GHRH) as well as somatostatin, which inhibits growth hormone release (see Chapter 17). Thus, the balance between the effects of these hypothalamic factors on the pituitary will determine the level of growth hormone release. The stimuli of growth hormone secretion can therefore act by increasing hypothalamic secretion of GHRH, decreasing secretion of somatostatin, or both. A third regulator of growth hormone secretion is ghrelin. The main site of ghrelin synthesis and secretion is the stomach, but it is also produced in the hypothalamus and has marked growth hormone–stimulating activity. In addition, it appears to be involved in the regulation of food intake (see Chapter 26).
Growth hormone secretion is under feedback control (see Chapter 16), like the secretion of other anterior pituitary hormones. It acts on the hypothalamus to antagonize GHRH release. Growth hormone also increases circulating IGF-I, and IGF-I in turn exerts a direct inhibitory action on growth hormone secretion from the pituitary. It also stimulates somatostatin secretion (Figure 18–6).
Feedback control of growth hormone secretion. Solid arrows represent positive effects and dashed arrows represent inhibition. GH, growth hormone; GHRH, growth hormone–releasing hormone; IGF-I, insulin-like growth factor-I; SS, somatostatin.
Stimuli Affecting Growth Hormone Secretion
The basal plasma growth hormone concentration ranges from 0 to 3 ng/mL in normal adults. However, secretory rates cannot be estimated from single values because of their irregular nature. Thus, average values over 24 h (see below) and peak values may be more meaningful, albeit difficult to assess in the clinical setting. The stimuli that increase and decrease growth hormone secretion are summarized in Table 18–3. The stimuli that increase secretion fall into three general categories: (1) conditions such as hypoglycemia and/or fasting in which there is an actual or threatened decrease in the substrate for energy production in cells, (2) conditions in which the amounts of certain amino acids are increased in the plasma, and (3) stressful stimuli. The response to glucagon has been used as a test of growth hormone reserve. Growth hormone secretion is also increased in persons deprived of rapid eye movement (REM) sleep (see Chapter 14) and inhibited during normal REM sleep.
TABLE 18–3Stimuli that affect growth hormone secretion in humans. ||Download (.pdf) TABLE 18–3 Stimuli that affect growth hormone secretion in humans.
Stimuli that increase secretion
Increase in circulating levels of certain amino acids
Infusion of arginine and some other amino acids
Going to sleep
L-dopa and α-adrenergic agonists that penetrate the brain
Apomorphine and other dopamine receptor agonists
Estrogens and androgens
Stressful stimuli (including various psychological stresses)
Stimuli that decrease secretion
Growth hormone and IGF-I
Glucose infusions lower plasma growth hormone levels and inhibit the response to exercise. The increase produced by 2-deoxyglucose is presumably due to intracellular glucose deficiency, since this compound blocks the catabolism of glucose-6-phosphate. Sex hormones induce growth hormone secretion, increase growth hormone responses to provocative stimuli such as arginine and insulin, and also serve as permissive factors for the action of growth hormone in the periphery. This likely contributes to the relatively high levels of circulating growth hormone and associated growth spurt in puberty. Growth hormone secretion is also induced by thyroid hormones. Growth hormone secretion is inhibited, on the other hand, by cortisol, FFA, and medroxyprogesterone.
Growth hormone secretion is increased by L-dopa, which increases the release of dopamine and norepinephrine in the brain, and by the dopamine receptor agonist apomorphine.