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Endocrine Regulation of Growth and Body Mass


Growth from the fertilized ovum to the adult is an exceedingly complex process involving both hyperplasia (an increase in the number of cells) and hypertrophy (an increase in the size of cells) as well as turnover of the cellular elements of body tissues. The timing and capacity for cell division vary among tissues. In the human central nervous system (CNS), neuronal division is essentially complete by 1 year of age, whereas bone, muscle, and fat cells continue to divide until later in childhood. Other tissues—such as skin, blood, and liver—retain the capacity for hyperplasia throughout life.

In humans, the genetic contribution to growth is evident from the observation that midparental height (i.e., the average of paternal and maternal heights) is one of the better predictors of a child's ultimate stature. For domestic animals, breeding based on desired growth characteristics has been a mainstay of animal husbandry for millennia. For humans, in whom such planned breeding does not occur, body-height differences among different populations suggest a genetic contribution. Even more striking are some of the differences seen with specific genetic mutations that affect skeletal growth (e.g., achondroplasia). The basis of these population height differences, and those related to genetic syndromes, is beyond the scope of this chapter. Rather we will focus on nutritional and hormonal processes in which physiological regulation appears to play an important role across individuals. The impact of environmental and nutritional factors, such as emotional or nutritional deprivation, on growth is most profound when it occurs during periods of tissue hyperplasia, most critically during the first 2 years of life.

In this chapter, the first two subchapters deal with factors that affect linear growth, whereas the third deals with factors that regulate body mass. This division is somewhat artificial because changes in linear growth and body mass often occur simultaneously. The control of linear growth in humans depends on multiple hormones, including growth hormone (GH), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), insulin, thyroid hormones, glucocorticoids, androgens, and estrogens. Among these, GH and IGF-1 have been implicated as the major determinants of growth in normal postuterine life. However, deficiencies (or excesses) of each of the other hormones can seriously affect the normal growth of the musculoskeletal system as well as the growth and maturation of other tissues. The control of body mass depends on many newly discovered humoral factors made in adipose tissue, intestine, hypothalamus, and other tissues that regulate appetite and energy expenditure.

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 N48-1 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

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

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.

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.

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.

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.

Figure 48-3, Synthesis and release of GHRH and SS, and the control of GH release. GHRH raises [cAMP] i and [Ca 2+ ] i in the somatotrophs and thereby stimulates release of GH stored in secretory granules. SS inhibits adenylyl cyclase (AC), lowers [Ca 2+ ] 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 Gα s , 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 Ca 2+ channels in the plasma membrane and causes [Ca 2+ ] i to rise. This increase in [Ca 2+ ] 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. N48-2 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

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

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 Gα i , which inhibits adenylyl cyclase. As a result, [Ca 2+ ] 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.

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