After studying this chapter, you should be able to:
Describe the structure of the pituitary gland and how it relates to its function.
Define the cell types present in the anterior pituitary and understand how their numbers are controlled in response to physiologic demands.
Understand the function of hormones derived from proopiomelanocortin in humans, and how they are involved in regulating pigmentation in humans, other mammals, and lower vertebrates.
Define the effects of the growth hormone in growth and metabolic function, and how insulin-like growth factor I (IGF-I) may mediate some of its actions in the periphery.
List the stimuli that regulate growth hormone secretion and define their underlying mechanisms.
Understand the relevance of pituitary secretion of gonadotropins and prolactin, and how these are regulated.
Understand the basis of conditions where pituitary function and growth hormone secretion and function are abnormal, and how they can be treated.
The pituitary gland, or hypophysis, lies in a pocket of the sphenoid bone at the base of the brain. It is a coordinating center for control of many downstream endocrine glands, some of which are discussed in subsequent chapters. In many ways, it can be considered to consist of at least two (and in some species, three) separate endocrine organs that contain a plethora of hormonally active substances. The anterior pituitary secretes thyroid-stimulating hormone (TSH, thyrotropin), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and growth hormone (see Figure 17–9), and receives almost all of its blood supply from the portal hypophysial vessels that pass initially through the median eminence, a structure immediately below the hypothalamus. This vascular arrangement positions the cells of the anterior pituitary to respond efficiently to regulatory factors released from the hypothalamus. Of the listed hormones, prolactin acts on the breast. The remaining five are, at least in part, tropic hormones; that is, they stimulate secretion of hormonally active substances by other endocrine glands or, in the case of growth hormone, the liver and other tissues (see below). The tropic hormones for some endocrine glands are discussed in the chapter on that gland: TSH in Chapter 19; and ACTH in Chapter 20. However, the gonadotropins FSH and LH, along with prolactin, are covered here.
The posterior pituitary in mammals consists predominantly of nerves that have their cell bodies in the hypothalamus, and stores oxytocin and vasopressin in the termini of these neurons, to be released into the bloodstream. The secretion of these hormones, as well as a discussion of the overall role of the hypothalamus and median eminence in regulating both the anterior and posterior pituitary, was covered in Chapter 17. In some species, there is also a well-developed intermediate lobe of the pituitary, whereas in humans it is rudimentary. Nevertheless, the intermediate lobe, as well as the anterior pituitary, contains hormonally active derivatives of the proopiomelanocortin (POMC) molecule that regulate skin pigmentation, among other functions (see below). To avoid redundancy, this chapter will focus predominantly on growth hormone and its role in growth and facilitating the activity of other hormones, along with a number of general considerations about the pituitary. The melanocyte-stimulating hormones (MSHs) of the intermediate lobe of the pituitary, α-MSH and β-MSH, will also be touched upon.
The anatomy of the pituitary gland is summarized in Figure 18–1 and discussed in detail in Chapter 17. The posterior pituitary is made up largely of the endings of axons from the supraoptic and paraventricular nuclei of the hypothalamus and arises initially as an extension of this structure. The anterior pituitary, on the other hand, contains endocrine cells that store its characteristic hormones and arises embryologically as an invagination of the pharynx (Rathke’s pouch). In species where it is well developed, the intermediate lobe is formed in the embryo from the dorsal half of Rathke’s pouch, but is closely adherent to the posterior lobe in the adult. It is separated from the anterior lobe by the remains of the cavity in Rathke’s pouch, the residual cleft.
FIGURE 18–1 Diagrammatic outline of the formation of the pituitary (left) and the various parts of the organ in the adult (right).
In the posterior lobe, the endings of the supraoptic and paraventricular axons can be observed in close relation to blood vessels. Pituicytes, stellate cells that are modified astrocytes, are also present.
As noted above, the intermediate lobe is rudimentary in humans and a few other mammalian species. In these species, most of its cells are incorporated in the anterior lobe. Along the residual cleft are small thyroid-like follicles, some containing a little colloid (see Chapter 19). The function of the colloid, if any, is unknown.
The anterior pituitary is made up of interlacing cell cords and an extensive network of sinusoidal capillaries. The endothelium of the capillaries is fenestrated, like that in other endocrine organs. The cells contain granules of stored hormone that are extruded from the cells by exocytosis. Their constituents then enter the capillaries to be conveyed to target tissues.
CELL TYPES IN THE ANTERIOR PITUITARY
Five types of secretory cells have been identified in the anterior pituitary by immunocytochemistry and electron microscopy. The cell types are the somatotropes, which secrete growth hormone; the lactotropes (also called mammotropes), which secrete prolactin; the corticotropes, which secrete ACTH; the thyrotropes, which secrete TSH; and the gonadotropes, which secrete FSH and LH. The characteristics of these cells are summarized in Table 18–1. Some cells may contain two or more hormones. It is also notable that the three pituitary glycoprotein hormones, FSH, LH, and TSH, while being made up of two subunits, all share a common α subunit that is the product of a single gene and has the same amino acid composition in each hormone, although their carbohydrate residues vary. The α subunit must be combined with a β subunit characteristic of each hormone for maximal physiologic activity. The β subunits, which are produced by separate genes and differ in structure, confer hormonal specificity (see Chapter 16). The α subunits are remarkably interchangeable and hybrid molecules can be created. In addition, the placental glycoprotein gonadotropin human chorionic gonadotropin (hCG) has α and β subunits (see Chapter 22).
TABLE 18–1 Hormone-secreting cells of the human anterior pituitary gland.
The anterior pituitary also contains folliculostellate cells that send processes between the granulated secretory cells. These cells produce paracrine factors that regulate the growth and function of the secretory cells discussed above. Indeed, the anterior pituitary can adjust the relative proportion of secretory cell types to meet varying requirements for different hormones at different life stages. This plasticity has recently been ascribed to the presence of a small number of pluripotent stem cells that persist in the adult gland.
PROOPIOMELANOCORTIN & DERIVATIVES
Intermediate-lobe cells, if present, and corticotropes of the anterior lobe both synthesize a large precursor protein that is cleaved to form a family of hormones. After removal of the signal peptide, this prohormone is known as proopiomelanocortin (POMC). This molecule is also synthesized in the hypothalamus, the lungs, the gastrointestinal tract, and the placenta. The structure of POMC, as well as its derivatives, is shown in Figure 18–2. In corticotropes, it is hydrolyzed to ACTH and β-lipotropin (LPH), plus a small amount of β-endorphin, and these substances are secreted. In the intermediate lobe cells, POMC is hydrolyzed to corticotropin-like intermediate-lobe peptide (CLIP), γ-LPH, and appreciable quantities of β-endorphin. The functions, if any, of CLIP and γ-LPH are unknown, whereas β-endorphin is an opioid peptide (see Chapter 7) that has the five amino acid residues of met-enkephalin at its amino terminal end. The melanotropins α- and β-MSH are also formed. However, the intermediate lobe in humans is rudimentary, and it appears that neither α-MSH nor β-MSH is secreted in adults. In some species, however, the melanotropins have important physiological functions, as discussed below.
FIGURE 18–2 Schematic representation of the preproopiomelanocortin molecule formed in pituitary cells, neurons, and other tissues. The numbers in parentheses identify the amino acid sequences in each of the polypeptide fragments. For convenience, the amino acid sequences are numbered from the amino terminal of ACTH and read toward the carboxyl terminal portion of the parent molecule, whereas the amino acid sequences in the other portion of the molecule read to the left to – 131, the amino terminal of the parent molecule. The locations of Lys–Arg and other pairs of basic amino acids residues are also indicated; these are the sites of proteolytic cleavage in the formation of the smaller fragments of the parent molecule. AL, anterior lobe; IL, intermediate lobe.
CONTROL OF SKIN COLORATION & PIGMENT ABNORMALITIES
Fish, reptiles, and amphibia change the color of their skin for thermoregulation, camouflage, and behavioral displays. They do this in part by moving black or brown granules into or out of the periphery of pigment cells called melanophores. The granules are made up of melanins, which are synthesized from dopamine (see Chapter 7) and dopaquinone. The movement of these granules is controlled by a variety of hormones and neurotransmitters, including α- and β-MSH, melanin-concentrating hormone, melatonin, and catecholamines.
Mammals have no melanophores containing pigment granules that disperse and aggregate, but they do have melanocytes, which have multiple processes containing melanin granules. Melanocytes express melanotropin-1receptors. Treatment with MSHs accelerates melanin synthesis, causing readily detectable darkening of the skin in humans in 24 h. As noted above, α- and β-MSH do not circulate in adult humans, and their function is unknown. However, ACTH binds to melanotropin-1 receptors. Indeed, the pigmentary changes in several human endocrine diseases are due to changes in circulating ACTH. For example, abnormal pallor is a hallmark of hypopituitarism. Hyperpigmentation occurs in patients with adrenal insufficiency due to primary adrenal disease. Indeed, the presence of hyperpigmentation in association with adrenal insufficiency rules out the possibility that the insufficiency is secondary to pituitary or hypothalamic disease because in these conditions, plasma ACTH is not increased (see Chapter 20). Other disorders of pigmentation result from peripheral mechanisms. Thus, albinos have a congenital inability to synthesize melanin. This can result from a variety of different genetic defects in the pathways for melanin synthesis. Piebaldism is characterized by patches of skin that lack melanin as a result of congenital defects in the migration of pigment cell precursors from the neural crest during embryonic development. Not only the condition but also the precise pattern of the loss is passed from one generation to the next. Vitiligo involves a similar patchy loss of melanin, but the loss develops progressively after birth secondary to an autoimmune process that targets melanocytes.
BIOSYNTHESIS & CHEMISTRY
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.
GROWTH HORMONE RECEPTORS
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.
FIGURE 18–3 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 P’s 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.
EFFECTS ON GROWTH
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 (see Clinical Box 18–1).
CLINICAL BOX 18–1
Gigantism & Acromegaly
Tumors of the somatotropes of the anterior pituitary (pituitary adenoma) 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.
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 recently become available and has been found to reduce plasma IGF-I and produce clinical improvement in cases of acromegaly that fail to 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 pharmacological therapy must often be continued after surgery to control ongoing symptoms.
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.
FIGURE 18–4 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 shown: a 21-aa extension of the C-terminus, a tetrapeptide substitution at Ser-29, and a tripeptide substitution of Ser-33.
The properties of IGF-I, IGF-II, and insulin 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 18–2 Comparison of insulin and the insulin-like growth factors.
DIRECT & INDIRECT ACTIONS OF GROWTH HORMONE
Our 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.
FIGURE 18–5 Direct and indirect actions of growth hormone (GH). The latter are mediated by the ability of growth hormone to induce production of IGF-I. (Courtesy of R Clark and N Gesundheit.)
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).
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 growth hormone secretion are summarized in Table 18–3. Most of them 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 subjects deprived of rapid eye movement (REM) sleep (see Chapter 14) and inhibited during normal REM sleep.
TABLE 18–3 Stimuli that affect growth hormone secretion in humans.
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.
PHYSIOLOGY OF GROWTH
Growth hormone, while being essentially unimportant for fetal development, is the most important hormone for postnatal growth. However, growth overall is a complex phenomenon that is affected not only by growth hormone and somatomedins, but also, as would be predicted by the previous discussion, by thyroid hormones, androgens, estrogens, glucocorticoids, and insulin. It is also affected, of course, by genetic factors, and it depends on adequate nutrition. It is normally accompanied by an orderly sequence of maturational changes, and it involves accretion of protein and an increase in length and size, not just an increase in weight (which could reflect the formation of fat or retention of salt and water rather than growth per se).
ROLE OF NUTRITION
The food supply is the most important extrinsic factor affecting growth. The diet must be adequate not only in protein content but also in essential vitamins and minerals (see Chapter 26) and in calories, so that ingested protein is not burned for energy. However, the age at which a dietary deficiency occurs appears to be an important consideration. For example, once the pubertal growth spurt has commenced, considerable linear growth continues even if caloric intake is reduced. Injury and disease, on the other hand, stunt growth because they increase protein catabolism.
Patterns of growth vary somewhat from species to species. Rats continue to grow, although at a declining rate, throughout life. In humans, two periods of rapid growth occur (Figure 18–7): the first in infancy and the second in late puberty just before growth stops. The first period of accelerated growth is partly a continuation of the fetal growth period. The second growth spurt, at the time of puberty, is due to growth hormone, androgens, and estrogens, and the subsequent cessation of growth is due in large part to closure of the epiphyses in the long bones by estrogens (see Chapter 21). After this time, further increases in height are not possible. Because girls mature earlier than boys, this growth spurt appears earlier in girls. Of course, in both sexes the rate of growth of individual tissues varies (Figure 18–8).
FIGURE 18–7 Rate of growth in boys and girls from birth to age 20.
FIGURE 18–8 Growth of different tissues at various ages as a percentage of size at age 20. The curves are composites that include data for both boys and girls.
It is interesting that at least during infancy, growth is not a continuous process but is episodic or saltatory. Increases in length of human infants of 0.5–2.5 cm in a few days are separated by periods of 2–63 days during which no measurable growth can be detected. The cause of the episodic growth is unknown.
The contributions of hormones to growth after birth are shown diagrammatically in Figure 18–9. Plasma growth hormone is elevated in newborns. Subsequently, average resting levels fall but the spikes of growth hormone secretion are larger, especially during puberty, so the mean plasma level over 24 h is increased; it is 2–4 ng/mL in normal adults, but 5–8 ng/mL in children. One of the factors stimulating IGF-I secretion is growth hormone, and plasma IGF-I levels rise during childhood, reaching a peak at 13–17 years of age. In contrast, IGF-II levels are constant throughout postnatal growth.
FIGURE 18–9 Relative importance of hormones in human growth at various ages. (Courtesy of Fisher DA.)
The growth spurt that occurs at the time of puberty (Figure 18–7) is due in part to the protein anabolic effect of androgens, and the secretion of adrenal androgens increases at this time in both sexes; however, it is also due to an interaction among sex steroids, growth hormone, and IGF-I. Treatment with estrogens and androgens increases the secretion of growth hormone in response to various stimuli and increases plasma IGF-I secondary to this increase in circulating growth hormone. This, in turn, causes growth.
Although androgens and estrogens initially stimulate growth, estrogens ultimately terminate growth by causing the epiphyses to fuse to the long bones (epiphysial closure). Once the epiphyses have closed, linear growth ceases (see Chapter 21). This is why patients with sexual precocity are apt to be dwarfed. On the other hand, men who were castrated before puberty tend to be tall because their estrogen production is decreased and their epiphyses remain open, allowing some growth to continue past the normal age of puberty.
In hypophysectomized animals, growth hormone increases growth but this effect is potentiated by thyroid hormones, which by themselves have no effect on growth. The action of thyroid hormones in this situation is therefore permissive to that of growth hormone, possibly via potentiation of the actions of somatomedins. Thyroid hormones also often appear to be necessary for the normal rate of growth hormone secretion; basal growth hormone levels are normal in hypothyroidism, but the response to hypoglycemia is frequently blunted. Thyroid hormones have widespread effects on the ossification of cartilage, the growth of teeth, the contours of the face, and the proportions of the body. Hypothyroid dwarfs (also known as cretins) therefore have infantile features (Figure 18–10). Patients who are dwarfed because of panhypopituitarism have features consistent with their chronologic age until puberty, but since they do not mature sexually, they have juvenile features in adulthood (Clinical Box 18–2).
FIGURE 18–10 Normal and abnormal growth. Hypothyroid dwarfs (cretins) retain their infantile proportions, whereas dwarfs of the constitutional type and, to a lesser extent, of the hypopituitary type have proportions characteristic of their chronologic age. See also Clinical Box 18–2. (Reproduced, with permission, from Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd ed. Thomas, 1966.)
CLINICAL BOX 18–2
The accompanying discussion of growth control should suggest several possible etiologies of short stature. It can be due to GHRH deficiency, growth hormone deficiency, or deficient secretion of IGF-I. Isolated growth hormone deficiency is often due to GHRH deficiency, and in these instances, the growth hormone response to GHRH is normal. However, some patients with isolated growth hormone deficiency have abnormalities of their growth hormone secreting cells. In another group of dwarfed children, the plasma growth hormone concentration is normal or elevated but their growth hormone receptors are unresponsive as a result of loss-of-function mutations. The resulting condition is known as growth hormone insensitivity or Laron dwarfism. Plasma IGF-I is markedly reduced, along with IGFBP 3, which is also growth hormone-dependent. African pygmies have normal plasma growth hormone levels and a modest reduction in the plasma level of growth hormone-binding protein. However, their plasma IGF-I concentration fails to increase at the time of puberty and they experience less growth than nonpygmy controls throughout the prepubertal period.
Short stature may also be caused by mechanisms independent of specific defects in the growth hormone axis. It is characteristic of childhood hypothyroidism (cretinism) and occurs in patients with precocious puberty. It is also part of the syndrome of gonadal dysgenesis seen in patients who have an XO chromosomal pattern instead of an XX or XY pattern (see Chapter 22). Various bone and metabolic diseases also cause stunted growth, and in many cases there is no known cause (“constitutional delayed growth”). Chronic abuse and neglect can also cause dwarfism in children, independent of malnutrition. This condition is known as psychosocial dwarfism or the Kaspar Hauser syndrome, named for the patient with the first reported case. Finally, achondroplasia, the most common form of dwarfism in humans, is characterized by short limbs with a normal trunk. It is an autosomal dominant condition caused by a mutation in the gene that codes for fibroblast growth factor receptor 3 (FGFR3). This member of the fibroblast growth receptor family is normally expressed in cartilage and the brain.
The treatment of dwarfism is dictated by its underlying cause. If treatment to replace the relevant hormone is commenced promptly in appropriate childhood cases, almost normal stature can often be attained. Thus, the availability of recombinant forms of growth hormone and IGF-I has greatly improved treatment in cases where these hormones are deficient.
The effect of insulin on growth is discussed in Chapter 24. Diabetic animals fail to grow, and insulin causes growth in hypophysectomized animals. However, the growth is appreciable only when large amounts of carbohydrate and protein are supplied with the insulin.
Adrenocortical hormones other than androgens exert a permissive action on growth in the sense that adrenalectomized animals fail to grow unless their blood pressures and circulations are maintained by replacement therapy. On the other hand, glucocorticoids are potent inhibitors of growth because of their direct action on cells, and treatment of children with pharmacologic doses of steroids slows or stops growth for as long as the treatment is continued.
Following illness or starvation in children, a period of catch-up growth (Figure 18–11) takes place during which the growth rate is greater than normal. The accelerated growth usually continues until the previous growth curve is reached, then slows to normal. The mechanisms that bring about and control catch-up growth are unknown.
FIGURE 18–11 Growth curve for a normal boy who had an illness beginning at age 5 and ending at age 7. The shaded area shows the range of normal heights for a given age. The red line shows actual growth of the boy studied. Catch-up growth eventually returned his height to his previous normal growth curve. (Modified from Boersma B, Wit JM: Catch-up growth. Endocr Rev 1997;18:646.)
PITUITARY GONADOTROPINS & PROLACTIN
FSH and LH are each made up of an α and a β subunit. They are glycoproteins that contain the hexoses mannose and galactose, the hexosamines N-acetylgalactosamine and N-acetylglycosamine, and the methylpentose fucose. They also contain sialic acid. The carbohydrate in the gonadotropin molecules increases their potency by markedly slowing their metabolism. The half-life of human FSH is about 170 min; the half-life of LH is about 60 min. Loss-of-function mutations in the FSH receptor cause hypogonadism. Gain-of-function mutations cause a spontaneous form of ovarian hyperstimulation syndrome, a condition in which many follicles are stimulated and cytokines are released from the ovary, causing increased vascular permeability and shock.
Human pituitary prolactin contains 199 amino acid residues and three disulfide bridges and has considerable structural similarity to human growth hormone and human chorionic somatomammotropin (hCS). The half-life of prolactin, like that of growth hormone, is about 20 min. Structurally similar prolactins are secreted by the endometrium and by the placenta.
The receptors for FSH and LH are G-protein coupled receptors coupled to adenylyl cyclase through a stimulatory G protein (Gs; see Chapter 2). In addition, each has an extended, glycosylated extracellular domain.
The human prolactin receptor resembles the growth hormone receptor and is one of the superfamily of receptors that includes the growth hormone receptor and receptors for many cytokines and hematopoietic growth factors (see Chapters 2 and 3). It dimerizes and activates the Janus kinase/signal transducers and activators of transcription (JAK–STAT) pathway and other intracellular enzyme cascades (Figure 18–3).
The testes and ovaries become atrophic when the pituitary is removed or destroyed. The actions of prolactin and the gonadotropins FSH and LH, as well as those of the gonadotropin secreted by the placenta, are described in detail in Chapters 22 and 23. In brief, FSH helps maintain the spermatogenic epithelium by stimulating Sertoli cells in the male and is responsible for the early growth of ovarian follicles in the female. LH is tropic for the Leydig cells and, in females, is responsible for the final maturation of the ovarian follicles and estrogen secretion from them. It is also responsible for ovulation, the initial formation of the corpus luteum, and secretion of progesterone.
Prolactin causes milk secretion from the breast after estrogen and progesterone priming. Its effect on the breast involves increasing mRNA levels and subsequent production of casein and lactalbumin. However, the action of the hormone is not exerted on the cell nucleus and is prevented by inhibitors of microtubules. Prolactin also inhibits the effects of gonadotropins, possibly by an action at the level of the ovary. It also prevents ovulation in lactating women. The function of prolactin in normal males is unsettled, but excess prolactin secreted by tumors causes impotence.
REGULATION OF PROLACTIN SECRETION
The regulatory factors for prolactin secretion by the pituitary overlap, in part, with those causing secretion of growth hormone, but there are important differences, and some stimuli increase prolactin secretion while decreasing that of growth hormone (and vice versa) (Table 18–4). The normal plasma prolactin concentration is approximately 5 ng/mL in men and 8 ng/mL in women. Secretion is tonically inhibited by the hypothalamus, and section of the pituitary stalk leads to an increase in circulating prolactin. Thus, the effect of the hypothalamic prolactin-inhibiting hormone, dopamine, must normally be greater than the effects of the various hypothalamic peptides with prolactin-releasing activity. In humans, prolactin secretion is increased by exercise, surgical and psychologic stresses, and stimulation of the nipple (Table 18–4). The plasma prolactin level rises during sleep, the rise starting after the onset of sleep and persisting throughout the sleep period. Secretion is increased during pregnancy, reaching a peak at the time of parturition. After delivery, the plasma concentration falls to nonpregnant levels in about 8 days. Suckling produces a prompt increase in secretion, but the magnitude of this rise gradually declines after a woman has been nursing for more than 3 months. With prolonged lactation, milk secretion occurs with prolactin levels that are in the normal range.
TABLE 18–4 Comparison of factors affecting the secretion of human prolactin and growth hormone.
L-Dopa decreases prolactin secretion by increasing the formation of dopamine; bromocriptine, and other dopamine agonists inhibit secretion because they stimulate dopamine receptors. Chlorpromazine and related drugs that block dopamine receptors increase prolactin secretion. Thyrotropin-releasing hormone (TRH) stimulates the secretion of prolactin in addition to TSH, and additional polypeptides with prolactin-releasing activity are present in hypothalamic tissue. Estrogens produce a slowly developing increase in prolactin secretion as a result of a direct action on the lactotropes.
It has now been established that prolactin facilitates the secretion of dopamine in the median eminence. Thus, prolactin acts in the hypothalamus in a negative feedback fashion to inhibit its own secretion.
EFFECTS OF PITUITARY INSUFFICIENCY
CHANGES IN OTHER ENDOCRINE GLANDS
The widespread changes that develop when the pituitary is removed surgically or destroyed by disease in humans or animals are predictable in terms of the known hormonal functions of the gland. In hypopituitarism, the adrenal cortex atrophies, and the secretion of adrenal glucocorticoids and sex hormones falls to low levels. Stress induced increases in aldosterone secretion are absent, but basal aldosterone secretion and increases induced by salt depletion are normal, at least for some time. Since no mineralocorticoid deficiency is present, salt loss and hypovolemic shock do not develop, but the inability to increase glucocorticoid secretion makes patients with pituitary insufficiency sensitive to stress. The development of salt loss in long-standing hypopituitarism is discussed in Chapter 20. Growth is inhibited (see above). Thyroid function is depressed to low levels, and cold is tolerated poorly. The gonads atrophy, sexual cycles stop, and some of the secondary sex characteristics disappear.
Hypophysectomized animals have a tendency to become hypoglycemic, especially when fasted. Hypophysectomy ameliorates diabetes mellitus (see Chapter 24) and markedly increases the hypoglycemic effect of insulin. This is due in part to the deficiency of adrenocortical hormones, but hypophysectomized animals are more sensitive to insulin than adrenalectomized animals because they also lack the anti-insulin effect of growth hormone.
Although selective destruction of the supraoptic–posterior pituitary causes diabetes insipidus (see Chapter 17), removal of both the anterior and posterior pituitary usually causes no more than a transient polyuria. In the past, there was speculation that the anterior pituitary secreted a “diuretic hormone,” but the amelioration of the diabetes insipidus is actually explained by a decrease in the osmotic load presented for excretion. Osmotically active particles hold water in the renal tubules (see Chapter 38). Because of the ACTH deficiency, the rate of protein catabolism is decreased in hypophysectomized animals. Because of the TSH deficiency, the metabolic rate is low. Consequently, fewer osmotically active products of catabolism are filtered and urine volume declines, even in the absence of vasopressin. Growth hormone deficiency contributes to the depression of the glomerular filtration rate in hypophysectomized animals, and growth hormone increases the glomerular filtration rate and renal plasma flow in humans. Finally, because of the glucocorticoid deficiency, there is the same defective excretion of a water load that is seen in adrenalectomized animals. The “diuretic” activity of the anterior pituitary can thus be explained in terms of the actions of ACTH, TSH, and growth hormone.
When growth hormone deficiency develops in adulthood, it is usually accompanied by deficiencies in other anterior pituitary hormones. The deficiency of ACTH and other pituitary hormones with MSH activity may be responsible for the pallor of the skin in patients with hypopituitarism. There may be some loss of protein in adults, but wasting is not a feature of hypopituitarism in humans, and most patients with pituitary insufficiency are well nourished.
CAUSES OF PITUITARY INSUFFICIENCY IN HUMANS
Tumors of the anterior pituitary cause pituitary insufficiency. Suprasellar cysts, remnants of Rathke’s pouch that enlarge and compress the pituitary, are another cause of hypopituitarism. In women who have an episode of shock due to postpartum hemorrhage, the pituitary may become infarcted, with the subsequent development of postpartum necrosis (Sheehan syndrome). The blood supply to the anterior lobe is vulnerable because it descends on the pituitary stalk through the rigid diaphragma sellae, and during pregnancy the pituitary is enlarged. Pituitary infarction is usually extremely rare in men.
The pituitary gland plays a critical role in regulating the function of downstream glands, and also exerts independent endocrine actions on a wide variety of peripheral organs and tissues. It consists of two functional sections in humans: the anterior pituitary, which secretes mainly tropic hormones; and the posterior pituitary, which contains nerve endings that release oxytocin and vasopressin. The intermediate lobe is prominent in lower vertebrates but not in humans or other mammals.
Corticotropes of the anterior lobe synthesize proopiomelanocortin, which is the precursor of ACTH, endorphins, and melanotropins. The latter have a critical role in the control of skin coloration in fish, amphibians, and reptiles, whereas ACTH is a primary regulator of skin pigmentation in mammals.
Growth hormone is synthesized by somatotropes. It is secreted in an episodic fashion in response to hypothalamic factors, and secretion is subject to feedback inhibition. A portion of the circulating pool is protein-bound.
Growth hormone activates growth and influences protein, carbohydrate, and fat metabolism to react to stressful conditions. Many, but not all, of the peripheral actions of growth hormone can be attributed to its ability to stimulate production of IGF-I.
Growth reflects a complex interplay of growth hormone, IGF-I, and many other hormones as well as extrinsic influences and genetic factors. The consequences of over- or underproduction of such influences depends on whether this occurs before or after puberty. Deficiencies in components of the growth hormone pathway in childhood lead to dwarfism; overproduction results in gigantism, acromegaly, or both.
The pituitary also supplies hormones that regulate reproductive tissues and lactation—follicle-stimulating hormone, luteinizing hormone, and prolactin. Prolactin, in particular, is regulated by many of the factors that also regulate growth hormone secretion, although specific regulators may have opposing effects.
For all questions, select the single best answer unless otherwise directed.
1. A neuroscientist is studying communication between the hypothalamus and pituitary in a rat model. She interrupts blood flow through the median eminence and then measures circulating levels of pituitary hormones following appropriate physiological stimulation. Secretion of which of the following hormones will be unaffected by the experimental manipulation?
A. Growth hormone
C. Thyroid stimulating hormone
D. Follicle-stimulating hormone
2. Which of the following pituitary hormones is an opioid peptide?
A. α-melanocyte-stimulating hormone (α-MSH)
D. Growth hormone
3. During childbirth, a woman suffers a serious hemorrhage and goes into shock. After she recovers, she displays symptoms of hypopituitarism. Which of the following will not be expected in this patient?
D. Low basal metabolic rate
E. Intolerance to stress
4. A scientist finds that infusion of growth hormone into the median eminence of the hypothalamus in experimental animals inhibits the secretion of growth hormone and concludes that this proves that growth hormone feeds back to inhibit GHRH secretion. Do you accept this conclusion?
A. No, because growth hormone does not cross the blood–brain barrier.
B. No, because the infused growth hormone could be stimulating dopamine secretion.
C. No, because substances placed in the median eminence could be transported to the anterior pituitary.
D. Yes, because systemically administered growth hormone inhibits growth hormone secretion.
E. Yes, because growth hormone binds GHRH, inactivating it.
5. The growth hormone receptor
A. activates Gs.
B. requires dimerization to exert its effects.
C. must be internalized to exert its effects.
D. resembles the IGF-I receptor.
E. resembles the ACTH receptor.
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