Medical Physiology, 3rd Edition

Growth Hormone

GH, secreted by somatotrophs in the anterior pituitary, is the principal endocrine regulator of growth

Individuals with excessive GH secretion during childhood develop gigantism, and those with a deficiency of GH develop pituitary dwarfism. It is thus quite clear that GH profoundly affects somatic size. Dramatic examples of the somatotrophic action of GH can be found in the descriptions of General Tom Thumb imageN48-1 and the Alton giant. GH deficiency resulted in Tom Thumb's achieving an adult height of ~1.0 m. In contrast, the Alton giant had a GH-secreting pituitary tumor present from early childhood and reached an adult height of >2.7 m. It is important that, in both cases, the abnormality of GH secretion was present from early life. Children with GH deficiency are of normal size at birth and only subsequently fall behind their peers in stature.

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General Tom Thumb

Contributed by Emile Boulpaep, Walter Boron

Charles S. Stratton (1838–1883), whose stage name was General Tom Thumb, was a famous performer in the P.T. Barnum circus. Stratton's maternal and paternal grandmothers were twin sisters of short stature. At birth, Stratton was somewhat larger than average (4.3 kg, or 9 pounds, 8 ounces) and he continued to grow normally until about 6 months of age, when he was 64 cm (25 inches) tall and weighed 6.8 kg (15 pounds). After that, he virtually ceased to grow for several years, although he was otherwise completely normal. He had siblings of normal size.

At the age of 9, Stratton began to grow very slowly, reaching the height of 74 cm (2 feet, 5 inches) at age 13 and 82.6 cm (2 feet, 8.5 inches) at age 18. At age 25, Stratton married Mercy Lavinia Bumpus (stage name, Lavinia Warren), who was also a short person. They had no children, and the cause of Stratton's short stature is not known.

The American circus impresario P.T. Barnum heard of Stratton and recruited him for his circus when Stratton was age 5. Barnum coached Stratton, who became a song-and-dance man and comedian. Tours of both the United States and Europe were great successes, and Stratton became an international celebrity and, under the guidance of Barnum, a wealthy man.

References

Wikipedia. s.v. General Tom Thumb. Last modified May 13, 2015.  http://en.wikipedia.org/wiki/General_Tom_Thumb [Accessed June 5, 2015].

Wikipedia. s.v. Lavinia Warren. Last modified May 6, 2015.  http://en.wikipedia.org/wiki/Lavinia_Warren [Accessed June 5, 2015].

A deficiency of GH beginning in adult life does not result in any major clinical illness. However, it is now appreciated that replacement of GH (clinically available as a recombinant protein) in adults with GH deficiency leads to increased lean body mass, decreased body fat, and perhaps an increased sense of vigor or well-being. An excess of GH after puberty results in the clinical syndrome of acromegaly (from the Greek akron [top] + megas [large]). This condition is characterized by the growth of bone and many other somatic tissues, including skin, muscle, heart, liver, and the gastrointestinal (GI) tract. The lengthening of long bones is not part of the syndrome because the epiphyseal growth plates close at the end of puberty. Thus, acromegaly causes a progressive thickening of bones and soft tissues of the head, hands, feet, and other parts of the body. If untreated, these somatic changes cause significant morbidity and shorten life as a result of joint deformity, hypertension, pulmonary insufficiency, and heart failure.

GH is made by somatotrophs throughout the anterior pituitary (see pp. 978–979). Like other peptide hormones, GH is synthesized as a larger “prehormone” (Fig. 48-1). During processing through the endoplasmic reticulum and Golgi system, several small peptides are removed. GH exists in at least three molecular forms. The predominant form is a 22-kDa polypeptide with two intramolecular sulfhydryl bonds. Alternative splicing generates a 20-kDa form of GH. Other GH forms include a 45-kDa protein, which is a dimer of the 22-kDa form, as well as larger forms that are multimers of monomeric GH. There is little information to suggest that the different principal forms of GH (i.e., the 20- and 22-kDa versions) vary in their activity, but the 20-kDa form may exert fewer of the acute metabolic actions of GH. Once synthesized, GH is stored in secretory granules in the cytosol of the somatotrophs until secreted.

image

FIGURE 48-1 Synthesis of GH. Somatotrophic cells in the anterior pituitary are responsible for the synthesis of GH. The cell transcribes five exons to form GH mRNA for either the 22-kDa protein (191 amino acids) or the 20-kDa protein (176 amino acids). Alternative splicing in the third exon, which removes the RNA-encoding amino acids 32 to 46, is responsible for the two isoforms found in the pituitary. Both mRNAs have a signal sequence that causes them to be translated in the rough endoplasmic reticulum (ER) and enter the secretory pathway. Subsequent processing converts the two pre-pro-GHs first to the pro-GHs and then to the mature GHs. The cleavage of the pro sequence and disulfide-bond formation occur during transit through the Golgi bodies. The somatotroph stores mature GH in granules until GHRH stimulates the somatotroph to secrete the hormones. The 22-kDa version is the dominant form of GH.

GH is in a family of hormones with overlapping activity

GH appears to be a single-copy gene, but four other hormones have significant homology to GH. Most striking are three hormones made by the placenta: placental-variant GH (pvGH) and human chorionic somatomammotropins 1 and 2 (hCS1 and hCS2; Table 48-1). Human genes for these hormones are located in the GH gene cluster on the long arm of chromosome 17. The multiple genes in this cluster have an identical intron structure and encode proteins of similar size with substantial amino-acid sequence homology.

TABLE 48-1

Homology of GH to Chorionic Hormones and Prolactin

HORMONE

NUMBER OF AMINO ACIDS

HOMOLOGY (%)

CHROMOSOME

hGH (human growth hormone)

191

100

17

pvGH (placental-variant GH)

191

93

17

hCS1 (human chorionic somatomammotropin 1)

191

84

17

hCS2 (human chorionic somatomammotropin 2)

191

84

17

hPRL (human prolactin)

199

16

6

pvGH is a 191–amino-acid peptide that is 93% identical to the 22-kDa form of GH. With virtually the same affinity as GH for the hepatic GH receptor, pvGH mimics some of the biological actions of GH and may be an important modulator of systemic IGF-1 production during pregnancy. (As discussed below, a major action of GH is to stimulate secretion of IGF-1.)

The hCSs are also called human placental lactogens (hPLs). The affinity of the two forms of hCS for the GH receptor is 100- to 1000-fold less than that of either GH or pvGH. As a result, the hCSs are less effective in promoting production of IGF-1 or IGF-2. The somatomammotropins are primarily lactogenic, priming the breast for lactation after birth (see Table 56-6).

The pituitary hormone prolactin (PRL; see Table 48-1) is the fourth hormone with homology to GH. The principal physiological role of PRL involves promotion of milk production in lactating women (see pp. 1148–1150). PRL is made by lactotrophs in the anterior pituitary. Its homology to GH suggests that the two hormones, despite their divergent actions, arose from some common precursor by a gene-duplication event. The sequence homology between these proteins is underscored by the observation that GH and PRL have similar affinities for the PRL receptor. The converse is not true—that is, PRL has no significant affinity for the GH receptor and thus has no growth-promoting activity. As discussed below, the PRL and GH receptors are coupled to an intracellular signaling system that involves stimulation of the JAK family of tyrosine kinases (see p. 70) as an early postreceptor event.

Men, like women, make PRL throughout their lives. However, no physiological role for PRL in males has been defined. Both men and women with disorders involving hypersecretion of GH or PRL can develop galactorrhea (breast milk secretion). Although GH and PRL are normally secreted by distinct cell populations in the anterior pituitary, some benign GH-producing pituitary adenomas (i.e., tumors) secrete PRL along with GH.

Somatotrophs secrete GH in pulses

Whereas growth occurs slowly over months and years, the secretion of GH is highly episodic, varying on a minute-to-minute basis. Most physiologically normal children experience episodes or bursts of GH secretion throughout the day, most prominently within the first several hours of sleep. Underlying each peak in plasma levels of GH, illustrated for an adult in Figure 48-2, are bursts of many hundreds of pulses of GH secretion by the somatotrophs in the anterior pituitary. With the induction of slow-wave sleep, several volleys of GH pulses may occur; it is estimated that >70% of total daily GH secretion occurs during these periods. This pulsatile secretion underlines the prominent role of the CNS in the regulation of GH secretion and growth. The circulating GH concentrations may be up to 100-fold higher during the bursts of GH secretion (i.e., the peaks in Fig. 48-2) than during intervening periods. The pattern of bursts depends on sleep-wake patterns, not on light-dark patterns. Exercise, stress, high-protein meals, and fasting also cause a rise in the mean GH level in humans. In circumstances in which GH secretion is stimulated (e.g., fasting or consumption of a high-protein diet), the increased GH output results from an increase in the frequency—rather than the amplitude—of pulses of GH secretion by the somatotrophs.

image

FIGURE 48-2 Bursts in plasma levels of GH, sampled in the blood plasma of a 23-year-old woman every 5 minutes over a 24-hour period. Each peak in the plasma GH concentration reflects bursts of hundreds of GH-secretory pulses by the somatotrophs of the anterior pituitary. These bursts are most common during the first few hours of sleep. The integrated amount of GH secreted each day is higher during pubertal growth than in younger children or in adults. (Data from Hartman ML, Veldhuis JD, Vance ML, et al: Somatotropin pulse frequency and basal concentrations are increased in acromegaly and are reduced by successful therapy. J Clin Endocrinol Metab 70:1375, 1990.)

GH secretion is under hierarchical control by GH–releasing hormone and somatostatin

The coordination of GH secretion by the somatotrophs during a secretory pulse presumably occurs in response to both positive and negative hypothalamic control signals.

GH-Releasing Hormone

Small-diameter neurons in the arcuate nucleus of the hypothalamus secrete growth hormone–releasing hormone (GHRH), a 43–amino-acid peptide that reaches the somatotrophs in the anterior pituitary via the hypophyseal portal blood (Fig. 48-3). As the name implies, this neuropeptide promotes GH secretion by the somatotrophs. GHRH is made principally in the hypothalamus, but it can also be found in neuroectodermal tissue outside the CNS; it was first isolated and purified from a pancreatic islet cell tumor of a patient with acromegaly.

image

FIGURE 48-3 Synthesis and release of GHRH and SS, and the control of GH release. GHRH raises [cAMP]i and [Ca2+]i in the somatotrophs and thereby stimulates release of GH stored in secretory granules. SS inhibits adenylyl cyclase (AC), lowers [Ca2+]i, and thereby inhibits release of GH. PKA, protein kinase A.

GHRH Receptor

GHRH binds to a G protein–coupled receptor (GPCR) on the somatotrophs and activates Gαs, which in turn stimulates adenylyl cyclase (see pp. 56–57). The subsequent rise in [cAMP]i causes increased gene transcription and synthesis of GH. In addition, the rise in [cAMP]i opens Ca2+ channels in the plasma membrane and causes [Ca2+]i to rise. This increase in [Ca2+]i stimulates the release of preformed GH.

Ghrelin

A relatively newly discovered hormone, ghrelin consists of 28 amino acids. One of the serine residues is linked to an octanol group, and only this acylated form of the peptide is biologically active. imageN48-2 Distinct endocrine cells within the mucosal layer of the stomach release ghrelin in response to fasting. Endocrine cells throughout the GI tract also make ghrelin, although the highest ghrelin concentrations are in the fundus of the stomach. The arcuate nucleus of the hypothalamus also makes small amounts of ghrelin. Infusion of ghrelin either into the bloodstream or into the cerebral ventricles markedly increases growth hormone secretion. Indeed, ghrelin appears to be involved in the postmeal stimulation of growth hormone secretion. It has been more difficult to define the extent to which ghrelin—versus GHRH and somatostatin (SS)—contributes to the changes in normal growth hormone secretion in response to fasting, amino-acid feeding, and carbohydrate feeding. Ghrelin also is orexigenic (i.e., it stimulates appetite; see p. 1003), thereby contributing to body mass regulation as well as linear growth.

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Ghrelin

Contributed by Emile Boulpaep, Walter Boron

Circulating forms of ghrelin include both the acyl and deacylated species, and this has complicated efforts to define the physiological responses of ghrelin to dietary manipulation as well as the responses to exogenously administered hormone. Ghrelin has 28 amino acids and is also known as ghrelin-28. The sequence of human ghrelin (amino acids 24 to 51 of the full, immature peptide), using the single-letter code, is as follows: GSSFLSP EHQRVQQRKE SKKPPAKLQP R. Ghrelin-27 has only 27 amino acids, lacking the C-terminal arginine of ghrelin-28.

Reference

UniProt Knowledgebase [results for ghrelin].  http://www.uniprot.org/uniprot/?query=ghrelin&sort=score [Accessed September 2014].

Ghrelin Receptor

The hormone ghrelin binds to a GPCR designated GH secretagogue receptor 1a (GHSR1a). This receptor was first identified because it binds synthetic peptide ligands that stimulate GH secretion. In this regard, GHSR1a is like the GHRH receptor (GHRHR); however, GHSR1a does not bind GHRH.

Somatostatin

The hypothalamus also synthesizes SS, a 14–amino-acid neuropeptide. SS is made in the periventricular region of the hypothalamus and is secreted into the hypophyseal portal blood supply. It is a potent inhibitor of GH secretion. SS is also made elsewhere in the brain and in selected tissues outside the CNS, such as the pancreatic islet δ cells (see p. 1053) and D cells in the GI tract (see pp. 868–870 and Table 41-1). Within the CNS, the 14–amino-acid form of SS (SS-14) dominates. The GI tract predominantly expresses a 28–amino-acid splice variant; the C-terminal 14 amino acids of SS-28 are identical to those of SS-14.

It appears that the primary regulation of GH secretion is stimulatory, because sectioning the pituitary stalk, and thereby interrupting the portal blood flow from the hypothalamus to the pituitary, leads to a decline in GH secretion. Conversely, sectioning of the stalk leads to a rise in PRL levels, presumably because dopamine made in the hypothalamus normally inhibits PRL secretion in the anterior pituitary (see pp. 1149–1150). It also appears that the pulses of GH secretion are entrained by the pulsatile secretion of GHRH (as opposed to the periodic loss of SS inhibition).

SS Receptor

SS binds to a GPCR called SSTR found on somatotrophs and activates Gαi, which inhibits adenylyl cyclase. As a result, [Ca2+]i decreases, which diminishes the responsiveness of the somatotroph to GHRH. When somatotrophs are exposed to both GHRH and SS, the inhibitory action of SS prevails.

Both GH and IGF-1 negatively feed back on GH secretion by somatotrophs

In addition to being controlled by GHRH, ghrelin, and SS, somatotroph secretion of GH is under negative-feedback control via IGF-1. As discussed below, GH triggers the secretion of IGF-1 from GH target tissues throughout the body (Fig. 48-4, No. 1). Indeed, IGF-1 mediates many of the growth-promoting actions of GH. IGF-1 synthesized in tissues such as muscle, cartilage, and bone may act in a paracrine or autocrine fashion to promote local tissue growth. In contrast, circulating IGF-1, largely derived from hepatic secretion, exerts endocrine effects. Circulating IGF-1 suppresses GH secretion through both direct and indirect mechanisms.

image

FIGURE 48-4 GH and IGF-1 (also called somatomedin C) negative-feedback loops. Both GH and IGF-1 feed back—either directly or indirectly—on the somatotrophs in the anterior pituitary to decrease GH secretion. GH itself inhibits GH secretion (“short loop”). IGF-1, whose release is stimulated by GH, inhibits GH release by three routes, one of which is direct and two of which are indirect. The direct action is for IGF-1 to inhibit the somatotroph. The first indirect pathway is for IGF-1 to suppress GHRH release in the hypothalamus. The second is for IGF-1 to increase secretion of SS, which in turn inhibits the somatotroph.

First, circulating IGF-1 exerts a direct action on the pituitary to suppress GH secretion by the somatotrophs (see Fig. 48-4, No. 2), probably inhibiting GH secretion by a mechanism different from that of SS. In its peripheral target cells, IGF-1 acts through a receptor tyrosine kinase (see pp. 68–70) and not by either the Ca2+ or cAMP messenger systems. IGF-1 presumably acts by this same mechanism to inhibit GH secretion in somatotrophs.

Second, circulating IGF-1 inhibits GH secretion via two indirect feedback pathways, both targeting the hypothalamus. IGF-1 suppresses GHRH release (see Fig. 48-4, No. 3) and also increases SS secretion (see Fig. 48-4, No. 4).

Yet another feedback system, independent of IGF-1, reduces GH secretion. Namely, GH itself appears to inhibit GH secretion in a short-loop feedback system (see Fig. 48-4, No. 5).

GH has short-term anti-insulin metabolic effects as well as long-term growth-promoting effects mediated by IGF-1

Once secreted, most GH circulates free in the plasma. However, a significant fraction (~40% for the 22-kDa GH) is complexed to a GH-binding protein formed by proteolytic cleavage of the extracellular domain of GH receptors in GH target tissues. This protein fragment binds to GH with high affinity, thereby increasing the half-life of GH and competing with GH target tissues for GH. In the circulation, GH has a half-life of ~25 minutes.

GH Receptor

GH binds to a receptor (GHR) on the surface of multiple target tissues. The monomeric GHR is a 620–amino-acid protein with a single membrane-spanning segment. The molecular weight of GHR (~130 kDa) greatly exceeds that predicted from its amino-acid composition (~70 kDa) as a result of extensive glycosylation. Like other members of the type I cytokine receptor family, GHR is a tyrosine kinase–associated receptor (see pp. 70–71). When one GH molecule simultaneously binds to sites on two GHR monomers and acts as a bridge, the monomers dimerize (see Fig. 3-12D). Receptor occupancy increases the activity of a tyrosine kinase (JAK2 family) that is associated with, but is not an integral part of, the GH receptor. This tyrosine kinase triggers a series of protein phosphorylations that modulate target cell activity.

Short-Term Effects of GH

GH has certain short-term (minutes to hours) actions on muscle, adipose tissue, and liver that may not necessarily be related to the more long-term growth-promoting actions of GH. These acute metabolic effects (Table 48-2) include stimulation of lipolysis in adipose tissue, inhibition of glucose uptake by muscle, and stimulation of gluconeogenesis by hepatocytes. These actions oppose the normal effects of insulin (see pp. 1035–1050) on these same tissues and have been termed the anti-insulin or diabetogenic actions of GH. Chronic oversecretion of GH, such as occurs in patients with GH-producing tumors in acromegaly, is accompanied by insulin resistance and often by glucose intolerance or frank diabetes.

TABLE 48-2

Diabetogenic Effects of GH

TARGET

EFFECT

Muscle

↓ Glucose uptake

Fat

↑ Lipolysis

Liver

↑ Gluconeogenesis

Muscle, fat, and liver

Insulin resistance

Long-Term Effects of GH via IGF-1

Distinct from these acute actions of GH is its action to promote tissue growth by stimulating target tissues to produce IGFs. In 1957, Salmon and Daughaday reported that GH itself does not have growth-promoting action on epiphyseal cartilage (the site where longitudinal bone growth occurs). In those experiments, the addition of serum from normal animals, but not from hypophysectomized (GH-deficient) animals, stimulated cartilage growth in vitro (assayed as incorporation of radiolabeled sulfate into cartilage). The addition of GH to GH-deficient serum did not restore the growth-promoting activity seen with normal serum. However, when the GH-deficient animals were treated in vivo with GH, their plasma promoted cartilage growth in vitro. This finding led to the hypothesis that, in animals, GH provokes the secretion of another circulating factor that mediates the action of GH. Initially called sulfation factor because of how it was assayed, this intermediate was subsequently termed somatomedin because it mediates the somatic effects of GH. We now know that somatomedin is in fact two peptides resembling proinsulin and thus termed insulin-like growth factors 1 and 2 (Fig. 48-5). Indeed, the IGFs exert insulin-like actions in isolated adipocytes and can produce hypoglycemia in animals and humans. IGF-1 and IGF-2 are made in various tissues, including the liver, kidney, muscle, cartilage, and bone. As noted above, the liver produces most of the circulating IGF-1, which more closely relates to GH secretion than does IGF-2.

image

FIGURE 48-5 Structure of the IGFs. Insulin, IGF-1, and IGF-2 share three domains (A, B, and C), which have a high degree of amino-acid (AA) sequence homology. The C region is cleaved from insulin (as the C peptide) during processing, but is not cleaved from either IGF-1 or IGF-2. In addition, IGF-1 and IGF-2 also have a short D domain.