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CHAPTER 12 GROWTH HORMONE AND ITS DISORDERS

CHAPTER 12 GROWTH HORMONE AND ITS DISORDERS
Principles and Practice of Endocrinology and Metabolism

SECTION A ADENOHYPOPHYSIS

CHAPTER 12 GROWTH HORMONE AND ITS DISORDERS

GERHARD BAUMANN

Growth Hormone Genes
Growth Hormone Structure
Growth Hormone Receptor
Growth Hormone–Binding Protein
Somatotrope Development and Growth Hormone
Secretion

Neural Control

Growth Hormone–Releasing Hormone and the Growth Hormone–Releasing Hormone Receptor

Somatostatin and Somatostatin Receptors

Growth Hormone–Releasing Peptides and the Growth Hormone–Releasing Peptide Receptor

Feedback Control

Other Control Mechanisms

Regulation of Placental Growth Hormone Secretion
Regulation of the Growth Hormone Receptor and Binding Protein
Actions of Growth Hormone

Insulin-Like Growth Factors and Their Binding Proteins

Insulin-Like Growth Factor Receptor
Measurement of Plasma Growth Hormone

Dynamic Tests of Growth Hormone Secretion

Clinical Use of Insulin-Like Growth Factor-I and Insulin-Like Growth Factor–Binding Protein Measurements
Abnormal Secretion of Growth Hormone

Deficiency of Growth Hormone

Growth Hormone Insensitivity

Hypersecretion of Growth Hormone (Acromegaly)

Hypersensitivity to Growth Hormone
Chapter References

Growth hormone (GH) is a polypeptide hormone produced by the somatotrope cells in the pituitary gland. It is the master anabolic hormone and possesses numerous bioactivities related to somatic growth, body composition, and intermediary metabolism. Many of the biologic actions of GH are mediated through insulin-like growth factor-I (IGF-I), but GH also has direct effects independent of IGF-I. Unlike most other hormones, GH is species specific, not only in its structure but also partially in its function. Its “one-way species specificity” refers to the fact that primate GHs are active in lower (evolutionarily earlier) species, but GHs of lower species are inactive in primates, including humans. GH regulation and, in part, GH action also differ among species. This chapter focuses primarily on human GH and its biology.
GROWTH HORMONE GENES
In humans, GH is encoded by two genes on the long arm of chromosome 17.1 They are part of a gene-duplication cluster that also includes the genes for chorionic somatomammotropin (placental lactogen), a protein highly homologous with GH (Fig. 12-1). The GH genes are named GH-N (or GH-1) and GH-V (or GH-2); the former is expressed in the pituitary, the latter in the placenta. GH-V is also called placental GH. The two GH genes are similar in structure; both are composed of five exons and four introns; each spans ~1.6 kb.

FIGURE 12-1. Human growth hormone locus on chromosome 17q22-24. The top panel shows the organization of the locus with the two GH genes (GH-N and GH-V) and the three chorionic somatomammotropin genes (CS-L, CS-A, CS-B). CS-L is probably a pseudogene. The bottom panel shows the GH-N gene in more detail, with five exons and four introns. GH-N is expressed in the pituitary, the other genes in the locus exclusively in the placenta. (From Parks JS. Molecular biology of growth hormone. Acta Paediatr Scand 1989; 349[Suppl]:127.)

GROWTH HORMONE STRUCTURE
Human GH is heterogeneous and consists of several molecular variants (Fig. 12-2).2 The principal form is a 191-amino-acid, single-chain protein with a molecular weight of ~22,000. It is the most abundant form (~90%–95% of pituitary GH), generally referred to as “GH” or “22K GH.” Two disulfide loops are present, and the three-dimensional structure is a twisted bundle of four a-helices (Fig. 12-3).3 Two independent receptor-binding sites are located on opposite surfaces of GH, allowing for ligand-induced receptor dimerization (see later). GH-V (placental GH) has a similar primary structure; it differs from GH-N (22K GH) in 13 of the 191 amino-acid positions (see Fig. 12-2). One important difference is the glycosylation consensus site at asparagine 140; GH-V exists as a glycosylated as well as nonglycosylated protein. The second most abundant GH form after 22K GH is an mRNA splice variant that lacks an internal sequence of 15 amino acids. Its molecular weight is ~20,000, and hence it is known as “20K GH.” It accounts for 5% to 7% of pituitary GH. Other minor variants include an Na-acylated and two deamidated variants (see Fig. 12-2). Little is known about the bioactivities or significance of these minor GH forms. In addition to the monomeric forms of GH just described, GH also exists as an oligomeric series of up to at least pentameric GH.4 Both noncovalent and disulfide-linked oligomers occur, and homo- as well as heterooligomers composed of the various monomeric forms exist in the pituitary and plasma. The biologic significance of GH oligomers is unclear, but they likely act as modulators of overall GH activity because of their different affinities for the GH receptor. The existence of so many molecular forms of GH is one reason for the difficulty with GH measurements and the discrepant results obtained by different assays (see later).

FIGURE 12-2. Primary structure of human growth hormone and its variants. The polypeptide shown is GH-N (22K). Amino-acid substitutions in GH-V are indicated next to the involved residues. The sequence connected by the heavy line (residues 32–46) is deleted in 20K GH. The tree structure at Asn-140 denotes glycosylation in GH-V. The asterisks indicate sites of deamidation, the dot at the amino terminus acylation. (From Baumann G. Growth hormone heterogeneity: genes, iso-hormones, variants and binding proteins. Endocr Rev 1991; 12:424.)

FIGURE 12-3. Three-dimensional structure of human growth hormone (22K), depicted as a ribbon diagram. The four main a-helices are shown together with three minihelices within the connecting loops. Some residues mutated for technical purposes are indicated; they are not relevant in this context. (N, amino terminus; C, carboxy terminus.) (From Ultsch MH, Somers W, Kossiakoff AA, de Vos AM. The crystal structure of affinity-matured human growth hormone at 2 Å resolution. J Mol Biol 1994; 236:286.)

GROWTH HORMONE RECEPTOR
The GH receptor (GHR) is a 620-amino-acid, ~130 kDa, single-chain glycoprotein with a single transmembrane domain, a large extracellular domain containing the GH-binding site, and an intracellular domain involved in GH signaling (Fig. 12-4).5 The extracellular domain also occurs separately as a soluble GH-binding protein (GHBP, see later). The GHR is a member of the cytokine receptor family that also includes the receptors for prolactin, erythropoietin and other hematopoietic growth factors, many of the interleukins, and others.6 The GHR is encoded by a single gene located on the short arm of chromosome 5. The gene spans at least 87 kb and is divided into 10 exons and 9 introns.7 Exons 2–7 encode the extracellular domain, exon 8 the trans-membrane domain, and exons 9 and 10 the intracellular domain. The GHR is expressed ubiquitously, with the liver being the organ most enriched in GHRs. In addition to the full-length GHR, two variants of the GHR are found in humans. A version lacking the 22 amino acids encoded by exon 3 is differentially expressed among tissues8 and/or in different individuals.9 This internal deletion near the amino terminus has no known functional consequence. The second variant is a GHR truncated at nine amino acids beyond the transmembrane domain, so that it lacks most of the intracellular domain.10 This variant is also expressed ubiquitously. The absence of an intracellular domain renders this variant incapable of signaling and favors prolonged persistence on the cell membrane. The latter may be the reason why this receptor variant contributes substantially to GHBP generation (see later). This truncated GHR variant modulates GH action by forming heterodimers with full-length GHRs, thereby sequestering some of the GHRs in a nonfunctional state.

FIGURE 12-4. Schematic representation of the growth hormone receptor (GHR) complementary DNA (top) and protein (bottom). The GHR is encoded by 10 exons; exons 2–7 encode the extracellular domain, exon 8 the transmembrane domain, and exons 9 and 10 the cytoplasmic domain. The numbers in the upper panel denote the exons; those in the lower panel the amino acids. The transmembrane domain is shaded in black. (Adapted from Kelly PA, Djiane J, Postel-Vinay M-C, Edery M. The prolactin/growth hormone receptor family. Endocr Rev 1991; 12:235.)

GH initiates its action first by binding to the GHR through site 1 on one of its surfaces; this is then followed by binding of a second GHR to site 2 on the other surface of GH.11 This results in a complex containing two GHRs in association with GH (Fig. 12-5). This GH-induced dimerization of the GHR is critical for GHR signaling and GH action. The functional domains of the GHR are depicted in Figure 12-6. Intracellular signaling is initiated by binding of JAK2 (Janus kinase 2) to a proline-rich region (Box 1) in the proximal intracellular part of the GHR, followed by a JAK2-mediated tyrosine phosphorylation cascade involving JAK2 itself, the GHR, signal transducers and activators of transcription (Stats) 1, 3, and 5, insulin-receptor substrates (IRS) 1 and 2, components of the mitogen-activated protein kinase (MAPK), the protein kinase C, and phosphatidyl inositol-3 kinase pathways, and several other intracellular signaling and adapter proteins, not all of which are known (Fig. 12-7).12 Gene transcription is then activated through these pathways. Interestingly, as of this writing, the precise pathway responsible for activation of IGF-I gene transcription is not known.

FIGURE 12-5. Schematic representation of growth hormone (GH)– induced dimerization of two growth hormone receptors (GHRs). Binding occurs first through site 1 on GH, followed by binding of a second GHR to site 2 on GH. The dimerized GHR (2:1) complex (lower right) is active in transducing the GH signal. At very high (pharmacologic) GH concentrations (lower left), the ratio of GH to GHR is high enough to saturate GHRs through site 1 binding, with the GHR trapped in an inactive 1:1 complex. This occurs at GH levels that are not seen in vivo. However, recognition of the potential existence of an inactive 1:1 complex was important in developing a GH antagonist (see text on treatment for acromegaly). (hGH, human growth hormone.) (From Fuh G, Cunningham BC, Fukunaga R, et al. Rational design of potent antagonists to the growth hormone receptor. Science 1992; 256:1677.)

FIGURE 12-6. Functional domains of the growth hormone receptor (extracellular domain is on top). The proline-rich Box 1 is crucial for JAK2 (Janus kinase 2) binding and initiation of most of the signaling events. (C, extracellular cysteines, only one of which is free [not disulfide linked]; N, potential N-linked glycosylation sites; Y, intracellular tyrosines, important for phosphorylation and docking of signaling molecules; WSXWS, tryptophan-serine motif; Stat, signal transducer and activator of transcription; SHC, Src homology containing protein; MAPK, mitogen-activated protein kinase; Spi 2.1, serine protease inhibitor 2.1; IRS, insulin receptor substrate.) (From Argetsinger LS, Carter-Su C. Mechanisms of signaling by growth hormone receptor. Physiol Rev 1996; 76:1089.)

FIGURE 12-7. Intracellular signaling pathways of the growth hormone receptor (GHR) (partial rendition). Principal pathways are the signal transducer and activator of transcription (Stat), protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and insulin receptor substrate (IRS) pathways. The inner ellipse represents the nucleus. Transcriptional elements, their cognate transcription factors, and transactivated genes are shown. (GH, growth hormone; P, phosphorylated sites; JAK2, Janus kinase 2; PC, phosphatidyl choline; PLC, phospholipase C; DAG, diacylglycerol; PI3K, phosphatidyl-inositol-3 kinase.) (From Argetsinger LS, Carter-Su C. Mechanisms of signaling by growth hormone receptor. Physiol Rev 1996; 76:1089.)

The GHR binds GH variants with different affinities. The 20K variant as well as the oligomeric GH forms have lower affinity than monomeric 22K GH, but GH-V is equipotent to 22K GH. Little is known about the binding of the other GH variants.
GROWTH HORMONE–BINDING PROTEIN
The GHBP is the soluble, extracellular domain of the GHR. In humans and many other species, the GHBP is generated from the GHR by proteolysis; in rodents it is derived from the GHR gene via alternative splicing.13 The GHBP circulates in plasma in nanomolar concentrations, sufficient to complex a substantial part (~50%) of plasma GH. The serum GHBP level appears to reflect the GHR abundance of the organism, especially in the liver. The biologic significance or importance of the GHBP is not known; it is evolutionarily conserved throughout the vertebrates and is generated by different mechanisms in different species, suggesting an important role. The GHBP modulates GH action through a variety of mechanisms. It inhibits GH action by competing with the GHR for ligand and by generating “unproductive” heterodimers with the GHR at the cell surface, as opposed to the GHR homodimers necessary for signaling. The GHBP also prolongs the half-life of GH in the circulation by complexing GH, thereby delaying its elimination. The net effect of these modulatory activities in the intact organism is not well understood.
In the circulation, GH also binds (with low affinity) to one or more proteins related to a214-macroglobulin. This complex accounts for no more than 5% of total GH in serum.
SOMATOTROPE DEVELOPMENT AND GROWTH HORMONE
Several pituitary transcription factors are involved in pituitary somatotrope development. Their consideration is important here because mutations in their respective genes lead to abnormalities in the GH axis. The reader is referred to Chapter 8 and Chapter 11 for a full discussion of pituitary ontogeny. Developmental genes relevant to GH include the Prop-1, Pit-1 (also known as Pou1f1), and GH-releasing hormone receptor (GHRH-R) genes. These genes are expressed sequentially during anterior pituitary development; each is more restrictive in its impact on different cell types; and each is dependent on the activity of the preceding one.15 Prop-1 and Pit-1 are POU-homeodomain transcription factors, the GHRH-R is a seven transmembrane domain receptor signaling through the cyclic adenosine mono-phosphate (cAMP) pathway. Prop-1 is important for development of the gonadotrope, somatotrope, lactotrope, and thyroptrope lineages. Pit-1, under the direction of Prop-1, is involved in differentiation of somatotropes, lactotropes, and thyrotropes. The GHRH-R, which is exclusively expressed in somatotropes under the direction of Pit-1, is critical for the normal expansion of the somatotrope population. The GHRH-R is also necessary for GH synthesis and secretion (see later).
SECRETION
NEURAL CONTROL
GH secretion is under neural control from the hypothalamus through at least two and possibly three hypophysiotropic factors: GH-releasing hormone (GHRH), somatostatin, and probably ghrelin (see following section). The GHRH neurons are located primarily in the arcuate and ventromedial nuclei, and somatostatin neurons are located primarily in the anterior periventricular area of the hypothalamus. GHRH and somatostatin release are controlled by a complex and incompletely understood neural network, involving a-adrenergic, dopaminergic, serotoninergic, cholinergic, and histaminergic inputs. In general, a-adrenergic, dopaminergic, serotoninergic, and cholinergic signals stimulate GH secretion. The limbic system plays an important role in GH secretion. A full discussion of the neural pathways regulating GH secretion is beyond the scope of this chapter. From a practical standpoint, it is important to know the physiologic stimuli leading to GH secretion, the principal pharmacologic agents used to test GH secretory capacity, and the peripheral feedback control of GH secretion.
GROWTH HORMONE–RELEASING HORMONE AND THE GROWTH HORMONE–RELEASING HORMONE RECEPTOR
GHRH is a 40- to 44-amino-acid peptide isolated first from pancreatic tumors that produced it ectopically,16,17 and subsequently from the hypothalamus (Fig. 12-8). Its gene, located on chromosome 20q, encodes a 108-amino-acid precursor from which GHRH is derived by proteolytic cleavage. It is expressed in highest concentration in the hypothalamus, but also in other parts of the brain, in the gut, and in other tissues. The extrahy-pothalamic role of GHRH is largely unknown; it may act as a sleep inducer. GHRH is released from the median eminence into the pituitary portal system and is the principal stimulatory hypophysiotropic factor promoting GH secretion. (As mentioned earlier, GHRH is also important for the development of somatotrope cells15 and for GH synthesis.18) GHRH, on reaching the somatotropes, interacts with the GHRH-R, which is a seven transmembrane, Gsa-coupled receptor that signals through the cAMP and Ca2+-channel pathways (Fig. 12-9). Activation of these pathways effects GH release from secretory granules as well as GH gene transcription. The GHRH-R is expressed in a variety of tissues, but its biologic role in extrapituitary sites is unknown. GHRH is rapidly inactivated in plasma by an amino peptidase that cleaves the N-terminal dipeptide. Ectopic production of GHRH can occur in carcinoid and pancreatic islet tumors.

FIGURE 12-8. Amino-acid sequence of growth hormone–releasing hormone (GHRH) 1-40 (top) and 1-44 (bottom). GHRH 1-44 has four additional amino acids at the C-terminal end of the molecule and is amidated.

FIGURE 12-9. Primary structure of the growth hormone–releasing hormone (GHRH) receptor, showing the seven transmembrane helices. The location of a nonsense mutation responsible for familial GHRH-resistant dwarfism is also shown (see text on congenital growth hormone deficiency). (From Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab 1998; 83:4065.)

SOMATOSTATIN AND SOMATOSTATIN RECEPTORS
Somatostatin is a cyclical peptide that exists in two forms: somatostatin-14 and somatostatin-28, the latter being extended at the amino terminus (Fig. 12-10 see Chap. 169). In humans, both somatostatins are encoded by a single gene on the long arm of chromosome 3, and a 92-amino-acid precursor is differentially processed to the two somatostatin forms, in part in a tissue-specific manner. In the hypothalamus, somatostatin-14 is the predominant form. Somatostatin is widely expressed throughout the central nervous system, the gut, and the pancreas. In extrahypothalamic sites, somatostatin has inhibitory effects on insulin secretion, gut hormone secretion, gut motility, and pancreatic and gastrointestinal exocrine secretions. In the hypothalamic-pituitary system, somatostatin inhibits GH and thyroid-stimulating hormone (TSH) secretion. Five somatostatin receptor subtypes are known; normal human pituitary expresses subtypes 1, 2, and 5.19 These receptors are members of the seven transmembrane domain, G protein–coupled class. Interaction of somatostatin with its receptors induces coupling to Gi and Go proteins, which in turn inhibits cAMP production and Ca2+-channel fluxes, thereby blocking release of GH (and other hormones).19

FIGURE 12-10. Amino-acid sequences of somatostatin-14 (top) and somatostatin-28 (bottom). The cyclical nature is indicated by the Cys-Cys bond.

GROWTH HORMONE–RELEASING PEPTIDES AND THE GROWTH HORMONE–RELEASING PEPTIDE RECEPTOR
GHRPs are a class of short peptides (5–6 amino acids) that are extremely potent as pharmacologic GH secretagogues. The first prototypes (GHRP-5 and GHRP-6) were described in the early 1980s,20 and many peptide and nonpeptide analogs have since been synthesized. GHRPs are not entirely specific for GH; they also act to release adrenocorticotropic hormone (ACTH) and prolactin, although the effect on these hormones is relatively modest. The cloning of a specific GHRP receptor in 1996 moved this field from the pharmacologic to the physiologic realm,21 and a natural ligand, ghrelin, has been identified.21a The GHRP receptor is also a seven transmembrane domain, G protein–coupled receptor that interacts with Ga11 It is expressed in the hypothalamus and to a lesser degree in the pituitary. Ghrelin is expressed in the stomach and hypothalamus; it must be considered as a potential candidate for the regulation of GH secretion. Of interest is that its action on GH secretion is dependent on a functional GHRH system, and that GHRH and GHRP have synergistic actions in vivo. In contrast, the effect of GHRP on ACTH and prolactin release is independent of GHRH. The principal site of action of GHRP on the release of GH, ACTH, and prolactin is the hypothalamus, although for GH a direct, minor effect is also present at the pituitary level. The precise role of the GHRP system in the regulation of GH secretion remains to be determined.
FEEDBACK CONTROL
Negative feedback on GH secretion is exerted by IGF-I (a long feedback loop) and by GH itself (a short feedback loop). IGF-I inhibits GH secretion at both the hypothalamic and pituitary levels by influencing GHRH and somatostatin production (hypothalamus) and by interfering with GHRH action (pituitary). GH inhibits its own secretion by modulating GHRH and somatostatin secretion in the hypothalamus. These feedback effects are superimposed on the neural control mentioned earlier.
OTHER CONTROL MECHANISMS
Other important control mechanisms for GH secretion are estrogen- and age-dependent changes. Estrogen has a generally stimulating effect on GH secretion, which results in a distinct sexual dimorphism of GH secretion during the reproductive years. Estrogen can also be used to “prime” a patient to maximize response to pharmacologic stimuli. The estrogen effect may in part be mediated by induction of a peripheral GH-resistant state, with lowering of serum IGF-I levels.
Pronounced developmental changes occur in GH secretion over the life span. In late fetal and neonatal life, GH secretion is very high and partly unregulated, perhaps in part because of the immaturity of the GHR system and low IGF-I levels. After birth, GH secretion rapidly falls to childhood levels, to be up-regulated again during puberty in response to sex steroids. Thereafter, GH secretion declines progressively by ~15% per decade, reaching very low levels in old age. This process has been termed “somatopause” and is in part responsible for the body compositional changes associated with aging. Both genders are affected by this age-dependent decline.
The principal physiologic short-term regulators of GH secretion are (a) neural endogenous rhythm, (b) sleep, (c) stress, including exercise, and (d) nutritional and metabolic signals.
The integrated result of the multiple inputs into the control of GH secretion is a diurnal rhythm of pulsatile secretion that is fairly constant in periodicity but varies widely in amplitude. The highest peaks in serum GH are seen during phase IV (slow wave) sleep, typically 1 to 2 hours after falling asleep. Pulses of smaller amplitude occur throughout the day, on average approximately every 2 hours.22 Many of these pulses are too small to be measured in conventional assays, and perhaps too small to have much biologic activity. Women of reproductive age generally have higher amplitudes as well as higher inter-peak GH levels—an effect that has been attributed to estrogen (Fig. 12-11). The extent to which metabolic changes due to intermittent meals influence GH secretion is unclear; available data suggest that under physiologic circumstances, such effects are minor at best. However, fasting, malnutrition, and obesity have profound effects on GH production (see later). The variability of serum GH levels makes it clear that sampling at single, random time points cannot be used for diagnostic purposes, and that dynamic testing under standardized conditions or diurnal sampling is necessary to arrive at a diagnosis of GH under- or overproduction.

FIGURE 12-11. Characteristic diurnal profiles of serum growth hormone (GH) levels in a young man (top) and a young woman (bottom). Women of reproductive age have a higher baseline and a greater average pulse amplitude than men. The ordinate is logarithmic to emphasize the presence of small secretory peaks throughout the day; note that the units for GH are pg/mL. The black bar indicates the period of sleep; the shaded bar shows the 1 ng/mL level that represents the detection limit in many conventional assays; the triangles on top indicate the secretory events as defined by a pulse-detection program. (Adapted from Winer LM, Shaw MA, Baumann G. Basal plasma growth hormone levels in man: new evidence for rhythmicity of growth hormone secretion. J Clin Endocrinol Metab 1990; 70:1678.)

There is no known differential secretion or specific stimulus for any of the GH variants. Indeed, they appear to be cosecreted in response to a variety of physiologic or pharmacologic stimuli. However, they have different plasma half-lives, and hence their relative proportions in plasma may differ from that in the pituitary. The average plasma half-life of GH (representing mostly monomeric 22K GH) is ~17 minutes.23 The 20K variant and oligomeric forms have longer half-lives.
After secretion, GH binds to GHBP in the circulation. This occurs very rapidly, with maximal binding achieved within a few minutes. The amount of GH bound to GHBP varies, depending on the GHBP level in a given person, the GH concentration (which may partially saturate the GHBP), and the time after a secretory pulse. On the average, 40% to 50% of plasma GH is bound to the GHBP.24 The bound fraction has delayed clearance, dampens the oscillations of serum GH, and serves as a circulating GH reservoir. The GHBP level in serum is not influenced by GH pulses; it exhibits no or minimal diurnal variation.
REGULATION OF PLACENTAL GROWTH HORMONE SECRETION
GH-V or placental GH is secreted during pregnancy into the maternal (but not fetal) circulation. This process is not regulated by the factors just described for pituitary GH regulation. The principles regulating GH-V secretion are unknown; it may simply be released constitutively as a function of syncytiotrophoblast mass. Plasma GH-V levels increase progressively during the second trimester to reach a plateau in the third trimester (Fig. 12-12). Concomitantly, pituitary GH-N levels are suppressed, presumably via negative feedback by GH-V and IGF-I. GH-V binds to GHR with the same affinity as GH-N; its high plasma levels may be responsible for some of the fluid retention and changes in physical features seen in late pregnancy.

FIGURE 12-12. Plasma levels of the growth hormones GH-N and GH-V during pregnancy. Pituitary GH-N is gradually supplanted by placental GH-V. (hGH, human growth hormone.) (From Baumann G. Growth hormone heterogeneity: genes, isohormones, variants and binding proteins. Endocr Rev 1991; 12:424; as adapted from Frankenne F, Closset J, Gomez F, et al. The physiology of growth hormones [GHs] in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab 1988; 66:1171.)

REGULATION OF THE GROWTH HORMONE RECEPTOR AND BINDING PROTEIN
For reasons of accessibility, little is known about the regulation of GHRs in human tissues. Therefore, much of the information about GHR regulation is based on (a) animal studies and (b) GHBP measurements in humans, using the GHBP as a surrogate for the GHR. Based on the comparison between direct GHR data in animals and GHBP data in humans, the GHBP level in serum appears to be a reasonable index of GHR abundance in tissues, primarily the liver.
The main regulator of GHR/GHBP abundance is ontogeny. In fetal and neonatal life, GHR expression is very low, and serum GHBP levels are correspondingly low. This is a physiologic GH-resistant condition, with high GH and low IGF-I levels. Postnatally a rapid up-regulation of the GHR and GHBP occurs, coincident with the emergence of GH responsivity.25 This process continues throughout childhood, until in the late teens GHBP levels (and presumably GHR levels) reach adult levels. GHBP levels remain constant through adult life until approximately age 60, when a progressive decline ensues that continues until the tenth decade.26 This decline is accompanied by a decline in IGF-I levels and constitutes part of the somatopause. Thus, in old age the changes caused by the decreasing GH secretion are further amplified by the development of GH resistance. Similar changes in GHR expression have been shown in aging animals. Women of reproductive age have slightly higher GHBP levels than men.
Estrogens, particularly if given orally, up-regulate serum GHBP, whereas androgens tend to lower GHBP. Interestingly, no discernible change is seen in GHBP level during puberty in either sex. The effect of GH itself on the GHBP in humans is controversial. The majority of studies find no significant change in GHBP levels in GH deficiency or in response to GH treatment. However, some reports show an up-regulation, and others a down-regulation of GHBP by GH. On balance, the effect of GH on serum GHBP (and probably, hence, on GHR) in humans is neutral or at least inconsistent. This differs from the case in rodents, in which the GHR (and the GHBP) expression is up-regulated by GH. Another important regulator of GHR/GHBP expression is nutritional status, probably, at least in part, mediated by insulin. A strong positive correlation exists between body mass index and serum GHBP, and IGF-I levels and GH responsivity vary in parallel as a function of adiposity and nutritional status.13
ACTIONS OF GROWTH HORMONE
Growth hormone has numerous biologic actions, many occurring in concert to enhance protein anabolism and tissue accretion. GH can act directly as well as indirectly through IGF-I, also known as somatomedin C. The mitogenic and proliferative actions of GH are mediated through IGF-I, whereas some of the metabolic actions are direct GH effects. GH has no specific target organ; it acts on most if not all tissues through the ubiquitously expressed GHR.
INSULIN-LIKE GROWTH FACTORS AND THEIR BINDING PROTEINS
The existence of GH-dependent factors that might mediate the action of GH was first suggested by the report that SO4 incorporation into growth cartilage chondroitin sulfate was reduced by hypophysectomy, but that exposure of cartilage to GH in vitro could not correct the abnormality. In contrast, serum from animals treated with GH was highly effective in restoring SO4 uptake, implicating a GH-dependent “sulfation factor.”27 Sulfation factor was later renamed somatomedin, and the “somatomedin hypothesis” was born. It soon became clear that somatomedin was identical to “nonsuppressible insulin-like activity,” which led to the characterization of IGF-I and IGF-II. The IGFs are proinsulin-like molecules that are produced in many tissues in response to GH and other regulators. IGF-I production is highly GH-dependent, whereas IGF-II production is less dependent on GH. IGFs act both locally in a paracrine/autocrine fashion and distantly in a hormone-like mode. They have mitogenic and metabolic activities and act through the type I IGF receptor, which is structurally similar to the insulin receptor. Six binding proteins for IGF (IGFBP) are present in serum and interstitial fluid; they may either enhance or decrease IGF activity.28 In addition, three IGFBP-related proteins bind IGFs with low affinity,29 for a total of nine proteins in the IGFBP family. IGFBP-1 is insulin dependent and has primarily inhibitory activity in vivo. IGFBP-2 is inversely GH dependent; its biologic role is incompletely understood. IGFBP-3 is the major IGFBP in serum; it is highly GH dependent, and it serves primarily to retain IGFs in the circulation by forming a 150-kDa ternary complex involving IGF, IGFBP-3, and another GH-dependent protein called acid-labile subunit (ALS). This complex is responsible for the high IGF concentrations in serum and serves as a circulating IGF reservoir. Most of the circulating IGF is bound in this complex. IGFBP-4, IGFBP-5, and IGFBP-6 are in part associated with the extracellular matrix and modulate IGF action through restricting or enhancing IGF access to the IGF receptor. IGFBP structure and activity is modulated by proteases that cleave the IGFBPs, thereby decreasing IGF-binding affinity. Protease activity is regulated by a variety of physiologic and pathologic conditions. IGFBPs and their fragments may have activities of their own (such as antianabolic activity) that are independent of their IGF-binding properties. A full description of the complex IGF-IGFBP system is beyond the scope of this chapter; from a clinical standpoint, an understanding of IGFBP-3 and IGFBP-2 is most important because they can be used diagnostically.
INSULIN-LIKE GROWTH FACTOR RECEPTOR
IGF-I and IGF-II bind to and signal through the IGF receptor (also known as type I IGF receptor). IGF-II also binds to the mannose-6-phosphate/type II IGF receptor, but to date no convincing evidence exists that the lysosomal pathway connected to this receptor is relevant to GH action. The type I IGF receptor is structurally homologous to the insulin receptor; it has a tetrameric structure with two extracellular b-subunits covalently connected to two b-subunits through disulfide bonds. The b-subunits have intrinsic tyrosine kinase activity and signal through a phosphorylation cascade involving IRS-1 and IRS-2, PI3-kinase, MAPK, and other pathways. The IGF receptor differs functionally from the insulin receptor in that it promotes primarily mitogenic/proliferative rather than metabolic activities. Because both receptors share intracellular pathways, it is of liver, where it is expressed at very low levels. The IGF system is described in detail in Chapter 173.
Because of the widespread expression of the GHR, the IGFs, and the IGF receptor, discerning which of the ultimate biologic actions of GH are direct and which are IGF-mediated has been difficult. Table 12-1 lists the principal GH actions and attempts to assign them to direct and IGF-mediated pathways. In many cases, this assignment is tentative, and both direct and indirect mediation may occur.

TABLE 12-1. Bioactivities of Growth Hormone (GH)

The principal bioactivities of the GH/IGF system relevant to the intact organism and to clinical medicine are nitrogen retention, protein anabolism, linear growth, lipolysis, insulin antagonism (diabetogenesis), Na+ retention, and negative feedback on GH secretion (short- and long-loop feedback). GH is best viewed as the master postnatal anabolic hormone orchestrating a cascade of activities leading to lean body mass accretion. The exception is adipose tissue, in which GH is largely catabolic. Human GH has lactogenic properties because it can bind to prolactin receptors. This is not a property of animal GHs, and its biologic importance in humans is uncertain. Also unclear is the importance of GH for the immune system; no overt abnormality in immune function is seen in cases of GH deficiency or in GH resistance.
MEASUREMENT OF PLASMA GROWTH HORMONE
The measurement of GH in blood is problematic because of the heterogeneous nature of GH. This heterogeneity is one reason for the observation that different assay designs can yield different results for the same blood sample.30 Plasma GH is measured either by conventional polyclonal radioimmunoassay or by a variety of monoclonal immunoradiometric or immunoenzymatic assays. Monoclonal assays frequently yield lower readings than polyclonal assays. This is in part due to the fact that some of the GH variants are not fully reactive in monoclonal assays, but other, poorly understood matrix effects are also involved. The problem of nonreproducibility of results among assays and laboratories can present a diagnostic dilemma in the classification of a patient as GH deficient or normal. Discrepancies are particularly notable among monoclonal assays. The need exists for a universal standard and assay design that permits comparison of GH determinations among different laboratories.
DYNAMIC TESTS OF GROWTH HORMONE SECRETION
Because of the pulsatile nature of GH secretion, plasma GH levels vary widely in normal subjects. It follows that a single GH measurement is not diagnostic for an abnormality in the GH axis. Therefore, dynamic testing of the response of plasma GH to standardized provocative or inhibitory tests is mandatory for the evaluation of GH disorders. Table 12-2 lists the dynamic tests in clinical use. This topic has been comprehensively reviewed.31 Among the provocative tests, the insulin-tolerance test is considered the “gold standard,” as it is a potent and reliable stimulus for GH release. Its disadvantage is that induction of hypoglycemia can be risky, and, therefore, the test must be closely supervised. For the test to be valid, a drop in blood glucose by at least 50% from the starting level must be achieved. GHRH testing has not proven to be as useful as anticipated because the GH response is highly variable, presumably because of differences in prevailing somatostatin tone. Clonidine is used successfully in children, but in adults it is a relatively weak stimulus for GH release. In normal subjects, the highest serum GH levels are seen after combined GHRH-GHRP stimulation. However, the clinical utility of this potent test in the diagnosis of GH deficiency is not yet known.

TABLE 12-2. Dynamic Tests for Growth Hormone Secretion

For research purposes, circadian sampling of blood for GH measurements is probably the best procedure to assess spontaneous GH secretion. The frequency of sampling should be at least every 20 minutes for accurate estimation of secretion rate. This can be done over a 24-hour period or overnight, when most of the GH secretion occurs. A variant of circadian sampling is continuous blood withdrawal by a pump. This yields a pooled “average” GH level but does not permit detection of secretory pulses. These maneuvers are cumbersome and impractical for general diagnostic purposes; they are largely reserved for investigational use. An additional limitation is that the GH secretion rate is quite variable among normal subjects, and the boundary between normal and deficient GH secretion rates is ill defined.
Measurement of urinary GH excretion has been advocated as a possible estimate of GH secretion rate. This method is technically feasible, but only a small fraction (£0.01%) of the daily GH production is excreted in the urine. This, combined with substantial day-to-day variability and dependence on renal function, has made it difficult to establish urine GH determination as a reliable index of GH production rate. Measurement of urine GH as a clinical test has therefore been largely abandoned.
The GHRH-stimulation test cannot be used to distinguish reliably between hypothalamic and pituitary GH deficiency. This is similar to the failure of testing with other hypothalamic releasing hormones (gonadotropin-releasing hormone [GnRH], thyrotropin-releasing hormone [TRH], corticotropin-releasing hormone [CRH]) to clearly differentiate hypothalamic from pituitary disease.
Pituitary function tests must be interpreted in the context of other clinical assessments. They can yield misleading results in some conditions not associated with hypothalamic-pituitary disease. Examples are obesity, hypothyroidism, or hypercorticism, in which the GH response to all stimuli tends to be blunted. Conversely, malnutrition, catabolic conditions, or stress may be associated with elevated GH levels that are not normally suppressible.
CLINICAL USE OF INSULIN-LIKE GROWTH FACTOR-I AND INSULIN-LIKE GROWTH FACTOR–BINDING PROTEIN MEASUREMENTS
Plasma IGF-I can be used as a surrogate measurement for GH. Unlike GH, its plasma level fluctuates very little throughout the day. Because IGF-I is highly GH dependent, its serum level reflects GH secretory status and can be used as an index for “integrated GH secretion.” The same is true for IGFBP-3, another GH-dependent factor. However, such measurements must be interpreted in the context of other clinical information. IGF-I is also highly dependent on nutritional status and is influenced by age, catabolic disease, etc. IGF-I and IGFBP-3 levels are best used in conjunction with dynamic GH measurements or for longitudinal follow-up in conditions that are already diagnosed as primary GH disorders. IGFBP-2 is inversely GH dependent and may be used as an ancillary measurement. IGF-II, although GH dependent to some degree, has not proven to be of clinical use in the diagnosis of GH disorders. In the measurement of IGFs, separation of IGF from the IGFBPs before measurements is imperative to avoid spurious results due to interference of IGFBPs in the assay. Several strategies can be used to accomplish this, such as acid ethanol extraction, C18 column separation, and acid gel filtration.
ABNORMAL SECRETION OF GROWTH HORMONE
DEFICIENCY OF GROWTH HORMONE
GH deficiency results from various causes, and the clinical manifestations depend on the age of the patient when the disease first occurs. The condition may be hereditary or acquired, and GH deficiency may be isolated or combined with other pituitary hormone deficiencies. Subdividing GH deficiency into childhood onset and adult onset categories is useful, because some of the clinical manifestations are different.
ETIOLOGY
Congenital Growth Hormone Deficiency. Table 12-3 lists the causes of GH deficiency. Among the congenital causes, between 5% and 30% have a familial pattern, which suggests a genetic basis. Known genetic causes of combined pituitary hormone deficiency involve the transcription factors Prop-1 and Pit-1, both members of the POU-homeodomain family of proteins critical for tissue differentiation. These genes are sequentially expressed during pituitary ontogeny, and Pit-1 is dependent on the expression of Prop-1 (of which the full name is “Prophet of Pit-1”). Inactivating mutations in the PROP1 gene lead to defective pituitary development, with TSH, luteinizing hormone, follicle-stimulating hormone, GH, and prolactin deficiency.32 A two-base deletion in a hot spot in the PROP1 gene, with resulting frameshift, is the most common cause.33 The clinical phenotype is one of familial dwarfism, with hypothyroidism and hypogonadism. Of interest, pituitary enlargement frequently occurs in affected patients—a finding whose pathogenesis is not clear. Mutations in the PIT1 gene are another cause of combined pituitary hormone deficiency.34 At least eight different mutations have been described; most are recessively inherited, but some are dominant negative (i.e., the abnormal gene product interferes with that derived from the normal allele). Pit-1 is important for development of somatotropes, lactotropes, and thyrotropes; affected patients suffer from GH, prolactin, and TSH deficiency. They do not develop pituitary enlargement as is seen in patients with PROP1 mutations. Known genetic causes of isolated GH deficiency include inactivating mutations in the GHRHR gene and in the GHN gene. GHRH action is required for somatotrope proliferation (late in pituitary development) and for GH synthesis and secretion. A defective GHRHR impacts all these mechanisms, and affected patients have pituitary hypoplasia and severe isolated GH deficiency.35,36 The clinical phenotype is one of proportionate dwarfism with relative microcephaly, normal fertility, and normal lactation.36 Mutations in the GHN gene affect GH production directly.37 The GH locus is prone to deletions because of gene duplication, which includes homologous sequences in the regions flanking the duplicated genes. Deletions of 6.7, 7.0, and 7.6 kb are typical; affected homozygous patients have severe GH deficiency (termed type IA). A similar phenotype occurs with other severely inactivating mutations, such as nonsense and frameshift mutations. A milder form (termed type IB) is seen with less disabling mutations, such as missense mutations in which some, albeit abnormal, GH is produced. In type IA, secondary resistance to exogenous GH administration is seen frequently, but not always, because of the formation of high-titer anti-GH antibodies to the “foreign” GH protein. Patients with type IB, on the other hand, respond well to exogenous GH because they are immune tolerant to GH. A special case in this category is a bioinactive GH.38 Dominantly inherited GHN gene mutations (termed type II) are caused by splice-site mutations in one allele that result in skipping of exon 3, with the resultant abnormal GH protein exerting a deleterious (dominant negative) influence on the normal GH produced by the intact allele. Improper disulfide pairing/aggregation or deranged transport to secretory granules are postulated mechanisms. In one case, a mutant GH was shown to act as an antagonist at the level of the GHR.39 Yet another type of isolated GH deficiency is inherited in an X-linked manner (termed type III). The gene involved is unknown but resides close to the gene for “Bruton tyrosine kinase,” an enzyme that is crucial for B-lymphocyte function. Hence, this type of GH deficiency is usually associated with hypo- or agammaglobu-linemia. Interestingly, defects in the GHRH gene have not been identified to date, despite the fact that many cases of idiopathic GH deficiency are thought to be due to GHRH deficiency.

TABLE 12-3. Causes of Growth Hormone (GH) Deficiency

The majority of cases of congenital GH deficiency (isolated or combined) are sporadic; they are thought to be caused by birth trauma, cerebral insults, and congenital malformations or tumors affecting hypothalamic-pituitary development or function. Approximately 10% of such patients have abnormal magnetic resonance imaging (MRI) scans. In one family affected with two cases of septo-optic dysplasia, an inactivating mutation has been found in the gene encoding the early developmental transcription factor Hesx1, also known as Rpx (Rathke Pouch Homeobox).40 The incidence of GH deficiency is estimated as 1 per 4000 to 10,000 births.
Acquired Growth Hormone Deficiency. GH deficiency can be acquired at any time during the life span, depending on when a hypothalamic-pituitary lesion or insult occurs. As already indicated, normal aging is associated with declining GH secretion during adulthood, and senescence resembles progressive GH insufficiency. During the growing years, the hallmark of GH deficiency is growth retardation; in adult life, the signs are more subtle changes in body composition and metabolism. Because of the lack of obvious manifestations, GH deficiency in adults is often not recognized, being diagnosed only after a long delay, or not considered clinically important. Moreover, only recently has GH deficiency in adults become amenable to therapy.
With pituitary lesions, the pattern of loss of pituitary hormones tends to follow a certain order: GH, gonadotropins, and prolactin tend to be lost early, whereas TSH and ACTH are affected later. This may be related to the abundance and/or spatial distribution of the respective cell types, with somato-tropes being the most prevalent (accounting for ~50% of the anterior pituitary mass).
CLINICAL PRESENTATION AND DIAGNOSIS
In childhood, GH deficiency soon declares itself because of growth retardation. The GH dependence of somatic growth begins at or shortly after birth. If coexistent TSH deficiency is present, the resulting hypothyroidism contributes to and aggravates growth retardation. Organic causes for GH deficiency should be sought, but frequently no lesion is found, leading to the diagnosis of idiopathic GH deficiency. This entity is attributed to partial GHRH deficiency, although direct proof is difficult to obtain. Patients with idiopathic GH deficiency usually have blunted, but not absent, GH responses to secretagogues. As already mentioned, the boundaries between normal, insufficient, and deficient GH secretion are ill defined because GH secretion rates are highly variable in normal people. This may render the diagnosis of idiopathic GH deficiency difficult. Growth retardation due to GH deficiency results in proportionate dwarfism and a progressive deviation from the normal growth curve. Untreated severe isolated GH deficiency results in adult heights of 120–140 cm in males and 110–130 cm in females. Other manifestations of GH deficiency during childhood are hypoglycemia, micropenis, and craniofacial abnormalities with saddle nose and facial hypoplasia. Patients tend to be “chubby” because of increased adipose tissue, particularly in the truncal area. Bone maturation is delayed by several years, and puberty is delayed by 2 to 3 years. Postpubertal men have a characteristic, high-pitched voice. The impact of GH deficiency on somatic growth and development is described in detail in Chapter 18, Chapter 92 and Chapter 198 Figure 12-13 shows the phenotype of adult patients with isolated GH deficiency. GH deficiency must be differentiated from other forms of short stature (constitutional, idiopathic, familial, etc.) that are much more common.

FIGURE 12-13. A, Two siblings with familial isolated growth hormone (GH) deficiency. Note the proportionate short stature and normal sexual development. B, The “child-like,” finely wrinkled face of a 41-year-old man with isolated GH deficiency.

In adults, GH deficiency should be suspected when a pituitary or hypothalamic lesion is found, or when a history of childhood GH deficiency is present. Patients who had idiopathic GH deficiency during childhood may or may not be GH deficient as adults, so that retesting of GH secretion in adulthood is required. Approximately two-thirds of such patients are found to have normal GH secretion as adults.41 One explanation for this phenomenon is that GH secretion rates during childhood and particularly during puberty are higher than in adult life, and that a partial limitation in GH production may yield levels that are inadequate during the growth years but sufficient in adulthood. Patients with pituitary lesions should be tested for GH deficiency even in the absence of other pituitary hormone deficiencies because somatotrope dysfunction may be an early manifestation of pituitary failure. This has therapeutic consequences, because such patients may benefit from GH treatment. The clinical manifestations of the adult GH deficiency syndrome are listed in Table 12-4.

TABLE 12-4. Clinical Manifestations of Growth Hormone Deficiency in Adults

Diagnosis relies on the demonstration of an underlying cause (a pituitary or hypothalamic lesion, a genetic defect, or a history of radiation), on provocative tests of GH secretion, and on IGF-I measurement. A low serum IGFBP-3 and a high IGFBP-2 level can be used as corroborative indicators. The typical, but arbitrary, cutoff for a normal peak GH level in response to provocative tests is 5 to 7 ng/mL in a polyclonal assay, and 2.5 to 3.5 ng/mL in a monoclonal assay. The Growth Hormone Research Society Consensus Guidelines for adult GH deficiency define a cutoff of 3 ng/mL in response to an insulin-tolerance test as “severe GH deficiency,” with a gray zone between 3 and 5 ng/mL, using a polyclonal assay.42 These cutoffs cannot be absolute because of the problems inherent in the assays mentioned above, and because of interindividual variations in GH response. Furthermore, tests that are less potent than the insulin-tolerance test may yield a lower GH response. Therefore, provocative tests must be interpreted in the clinical context. A finding of a low serum IGF-I level is helpful in the absence of other causes for decreased IGF production, such as nutritional deprivation. However, difficulty arises because of the wide normal range for IGF-I levels. IGF-I levels are highly age dependent and must be judged against age-appropriate normative values. In very young children, in whom IGF-I levels are naturally low, differentiation of GH deficiency from normal production may be difficult based on the IGF-I level. In adults, particularly older adults, considerable overlap also exists between the normal IGF-I range and that seen in GH deficiency (Fig. 12-14).

FIGURE 12-14. Serum insulin-like growth factor-I (IGF-I) levels in adult hypopituitary patients, aged 17 to 77 years (closed circles), compared to those in age-matched normal controls (open circles). All patients had growth hormone deficiency, as assessed by the insulin-tolerance test, and deficiency of other pituitary hormones. Note the overlap between normal and hypopituitary IGF-I levels. (S, assay sensitivity for IGF-I [25 ng/mL]; n, number of subjects tested.) (Adapted from Hoffman DM, O’Sullivan AJ, Baxter RC, Ho KKY. Diagnosis of growth-hormone deficiency in adults. Lancet 1994; 343:1064.)

TREATMENT
GH deficiency can be treated successfully with recombinant human GH, given subcutaneously once daily at bedtime. The bedtime dosing is designed to at least partially mimic the normal GH secretory pulse occurring after sleep onset. The dose for children is 25 to 50 µg/kg per day; for adults it is 3 to 12 µg/kg per day. Studies have suggested that in adults administration of an absolute daily dose (e.g., 200–400 µg per day) may be more appropriate than dosing based on kilograms of body weight. This regimen is more physiologic because normal GH secretion is inversely related to adiposity, and weight-based dosing does not consider this. Women of reproductive age or those on estrogen treatment need higher GH doses to maintain normal IGF-I levels, as would be expected from the higher GH-secretion rates in normal women.
GH therapy is highly effective in reversing the manifestations of GH deficiency. The effect on children is growth acceleration to normal or even “catch-up” growth velocity, and normal adult height can be achieved provided that treatment starts early and is maintained until epiphyseal fusion occurs. Pediatric use of GH is described in detail in Chapter 18, Chapter 92 and Chapter 198. In adults, the principal effects are normalization of body composition (i.e., a decrease in adipose tissue, particularly visceral fat; Fig. 12-15), an increase in lean body mass and body fluid, an increase in bone mineral density, and a decrease in low-density lipoprotein cholesterol.43 Other effects, such as improved muscular strength, endurance, energy, and psychosocial well-being, have also been reported in many, but not all, studies. Several years are probably required to realize the full benefit of GH therapy in adults. GH therapy for adults has begun only in the past decade, and its ultimate outcome is still not fully known. One important unanswered question is whether the shortened life span of hypopituitary patients44 can be prolonged with GH therapy.44a

FIGURE 12-15. Transverse computed tomographic scan at the L3–L4 level before (A) and after 6 months of growth hormone therapy (B). Note the reduction of both visceral and subcutaneous adipose tissue (dark areas). (R, right; L, left.) (From Bengtsson B-A, Edén S, Lönn L, et al. Treatment of adults with growth hormone [GH] deficiency with recombinant human GH. J Clin Endocrinol Metab 1993; 76:309.)

GH dosing is monitored in children by observation of growth velocity and serum IGF-I, and in adults by serum IGF-I levels, which should be maintained in the age-appropriate normal range. Side effects are rare in children; adults, particularly the elderly, are more prone to side effects, such as transient edema, carpal tunnel syndrome, arthralgia, and myalgia, but these symptoms can be minimized or largely avoided by proper dosing. GH secretion naturally declines with age, and dosing accordingly should be adjusted based on age. Carbohydrate intolerance has not proved to be a major problem in GH-replacement therapy. Typically, insulin levels increase initially, but glucose levels remain normal. This is physiologically appropriate and inherent in the correction of the GH-deficient state. Nevertheless, glycemia should be monitored after institution of GH therapy, which may unmask a latent diabetic propensity. As adiposity diminishes over time, insulin levels tend to fall back to baseline values.
GROWTH HORMONE INSENSITIVITY
A condition that clinically resembles GH deficiency is GH insensitivity, which can range from absolute GH resistance to varying degrees of mild GH insensitivity. It may be congenital/genetic or acquired.
GENETIC CAUSES
Genetic GH resistance, also known as Laron syndrome, is due to inactivating mutations in the GHR gene.45 Inheritance is autosomal recessive. Over 250 patients have been reported worldwide; significant consanguineous clusters have been described in Israel, Ecuador, and the Bahamas. Over 35 different mutations (deletions and nonsense, splice-site, and missense mutations) have been identified to date. Most are found in the extracellular domain of the receptor and inactivate the GH binding site. Other mutations include one that interferes with receptor dimerization, some that result in skipping of exon 8 (which encodes the trans-membrane domain), and some that severely truncate the intra-cellular domain. Of interest is a mutation that has a dominant negative effect because the abnormal, truncated receptor interferes with normal receptor signaling owing to heterodimer formation between normal and mutant receptor.46 The type of mutation determines whether the GHBP activity in plasma is absent or low (the majority of cases), normal, or even high (e.g., when the mutant receptor lacks a transmembrane domain).47
The phenotype is similar to that of severe GH deficiency. Children are near-normal at birth but show all the signs and symptoms associated with GH deficiency described earlier. Facial dysplasia may be even more pronounced than in GH deficiency. Heterozygotes are physically normal. IGF-I and IGFBP-3 levels are very low, but in contrast to GH deficiency, GH levels are elevated, both in the basal state and after stimulation. This is due to lack of negative feedback on GH production by IGF-I and by GH. Treatment with GH is ineffective, but therapy with IGF-I has resulted in growth rates that approach, but do not quite reach, those seen with GH therapy in GH-deficient children. Numerous problems exist with IGF-I therapy, such as abnormal pharmacokinetics because of low IGFBP-3 levels, limited availability of IGF-I, and absence of direct GH effects, that render therapy for this rare condition difficult.
Milder heterozygous mutations or polymorphisms in the GH receptor have been suggested as a possible explanation of idiopathic short stature.48 However, in view of the fact that heterozygous relatives of Laron syndrome patients are of normal height, it is difficult to explain how milder heterozygous mutations would cause short stature.
Pygmies have a primary, possibly genetic, form of partial GH resistance. This has been attributed to low GHR expression, based on low serum GHBP levels.49 Pygmies may also have partial IGF-I insensitivity, as postulated from the lack of an IGF-mediated proliferative response of lymphocytes derived from pygmies.50 The exact reasons for pygmies’ short stature remain to be elucidated.
ACQUIRED CAUSES
Many medical conditions are associated with GH insensitivity of varying degrees (Table 12-5). These conditions are characterized by low IGF-I levels, elevated GH levels, and low GHBP levels. Decreased hepatic GHR expression has been demonstrated in corresponding animal models. GH insensitivity contributes to and aggravates catabolism in those disorders that are already prone to catabolism because of oversecretion of stress hormones such as glucocorticoids, catecholamines, and glucagon. To date, influencing the GH-resistant state has not been possible, except by treating the underlying cause. Attempts to overcome the resistance with large doses of exogenous GH have had mixed results, depending on the type of catabolic condition being treated. A study of GH treatment in critically ill patients resulted in a higher mortality. Therefore such therapy cannot be recommended at present except in the context of carefully controlled studies.

TABLE 12-5. Conditions Associated with Growth Hormone (GH) Resistance

HYPERSECRETION OF GROWTH HORMONE (ACROMEGALY)
Overproduction of GH, usually by a pituitary tumor, causes acromegaly in adults and pituitary gigantism in prepubertal children. Acromegaly is a disease of insidious onset that usually is not recognized until the progressive overgrowth of connective tissue and bone has caused striking changes of appearance. The prevalence of acromegaly is estimated to be ~1 in 20,000.51 Its peak incidence is between the fourth and sixth decades.
ETIOLOGY AND PATHOGENESIS
The great majority (>99%) of cases of acromegaly are caused by a pituitary adenoma, either pure somatotrope or occasionally somatomammotrope in origin. The adenoma is usually sporadic but may occur as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. Rarely, acromegaly may result from somatotrope hyperplasia, induced by excess production of GHRH from an ectopic source (carcinoids, islet cell tumors, small cell carcinoma) or by hamartomas or gangliocytomas in the hypothalamic or pituitary area. GHRH was first isolated from such an ectopic source in the pancreas,16,17 but only 50 cases of ectopic GHRH-induced acromegaly have been described.52 Only one clearly documented case exists of acromegaly due to ectopic production of GH (by an islet cell tumor).53 McCune-Albright syndrome is another disorder that can be associated with acromegaly and gigantism.
Although the role of a primary pituitary or hypothalamic disorder as the initiating cause of acromegaly was disputed for years, it is now clear that many GH-secreting tumors are monoclonal and harbor an activating mutation of the Gsa protein subunit. As indicated above, the GHRH-R signals through theGs-cAMP pathway, and constitutive activation of Gs essentially bypasses GHRH-regulated somatotrope growth, GH synthesis, and GH secretion. Thus, in a substantial proportion of tumors, a somatic mutation seems to be responsible for the disease.54 McCune-Albright syndrome, a disorder with widespread constitutive activation of Gsa, probably causes GH overproduction through the same mechanism.55 In MEN1, tumorigenesis is a function of the loss of both alleles of a tumor-suppressor gene, the menin gene.56 Thus, except in rare cases of ectopic (or eutopic) GHRH overproduction, acromegaly appears to be a primary pituitary disorder.
CLINICAL AND LABORATORY MANIFESTATIONS
The clinical manifestations of acromegaly relate to the hormonal effects of GH and IGF-I on the one hand, and to local tumor-mass effects on the other. Table 12-6 lists the principal clinical and laboratory findings recorded in a large series of patients with acromegaly; Figure 12-16, Figure 12-17 and Figure 12-18 illustrate typical features. The symptoms and signs of acromegaly can be divided into three categories: (a) physical changes related to excessive amounts of GH and IGF-I, (b) metabolic effects of excessive amounts of GH, and (c) local effects of the pituitary tumor.

TABLE 12-6. Clinical and Laboratory Findings in 57 Patients with Acromegaly

FIGURE 12-16. A 64-year-old man with acromegaly. Note the prominent jaw, the large zygomatic arches and supraorbital ridges. The bony overgrowth results in a comparative hollowing of the temporal region. The nose and ears are enlarged. The skin folds are exaggerated, the skin is tough and oily, and the sebaceous glands and pores are enlarged.

FIGURE 12-17. A–C, Progressive acromegalic changes in a 58-year-old man. Old photographs are useful to evaluate whether a diagnosis of acro-megaly should be considered or to document progression of the disease.

FIGURE 12-18. A 64-year-old man with acromegaly. Note the prominent jaw, the large zygomatic arches and supraorbital ridges. The bony overgrowth results in a comparative hollowing of the temporal region. The nose and ears are enlarged. The skin folds are exaggerated, the skin is tough and oily, and the sebaceous glands and pores are enlarged.

Identifying acromegaly on the basis of appearance alone can be difficult. Because these changes occur slowly, often only the examination of old photographs can confirm the suspicion and help determine the time of onset (see Fig. 12-17). A delay in diagnosis is unfortunate because a surgical cure is much more likely when the tumor is small, and the more prominent bony changes are only partially reversible. In experienced surgical hands, transsphenoidal adenomectomy is curative for the majority of microadenomas (<1 cm in diameter), but cures are more difficult to achieve for macroadenomas (see later). Somatotrope tumors have a propensity for local invasion, including of bone, which makes eradication of all cells extraordinarily difficult once the tumor has progressed beyond the boundaries of the pituitary gland.
The physical changes (see Fig. 12-16, Fig. 12-17 and Fig. 12-18 include a general coarsening of features. Acral growth of bone and soft tissues is seen (a finding that gave the disease its name). Patients typically have large, spadelike hands, with a characteristic swelling of subcutaneous tissues that is more doughy than edematous (see Fig. 12-18). This results in a change in ring, glove, and shoe size—key anamnestic elements that should be actively sought.
Bony overgrowth in the skull leads to frontal bossing, mandibular growth, prognathism, and dental malocclusion. Bony overgrowth leads to bone spurs in the spine and around the large joints, sometimes giving rise to spinal stenosis or other nerve compression syndromes. Carpal tunnel syndrome is a classic early sign of acromegaly; it is also seen with exogenous GH treatment for GH deficiency (see earlier). A barrel deformity of the chest may occur as a result of rib elongation and kyphosis. Laryngeal overgrowth and thickened vocal cords, together with cranial hyperpneumatization, causes a characteristic deep, sonorous voice. The tongue is large and hypertrophic, sometimes with dental impressions at its borders. Sleep apnea is a common finding, at least in part because of pharyngeal obstruction. The skin is coarse and oily, and skin tags are common. Patients complain of excessive sweating and body odor. Galactorrhea may be present in women. The large joints may show deformities, and the calvarium is thickened. Arthralgias and osteoarthritis-like arthropathies are common. General visceromegaly is present.
Cardiac enlargement commonly occurs, and abnormalities invariably are seen on tests of dynamic cardiac function.57 This probably results from a combination of direct effects of GH and IGF-I on myocardial growth and the sequelae of hypertension, hyperlipidemia, and diabetes, all of which are associated with acromegaly. Before effective means of treating acromegaly were available, premature cardiovascular death was responsible for a significantly shortened life span.
Acromegaly predisposes to colonic polyp formation,58 and the incidence of colon cancer is probably also increased.59
The metabolic effects of excess GH and IGF-I relate to sodium retention, insulin antagonism, phosphate retention, abnormal calcium metabolism, and heightened bone turnover. One-third of acromegalic patients have hypertension.60 Carbohydrate intolerance is common, and frank diabetes mellitus is seen in 10% to 20% of patients. Hyperlipidemias of various types occur in the presence and even absence of diabetes. Serum phosphorus levels are elevated, as are levels of 1,25-hydroxyvitamin D. There is increased calcium absorption and excretion, as well as hydroxyproline excretion as a manifestation of increased bone turnover.
Local tumor effects include headaches, visual field abnormalities due to optic chiasm compression, oculomotor paresis due to cavernous sinus invasion, galactorrhea due to stalk compression, and panhypopituitarism (uncommon). Headaches are characteristic for acromegaly, may be severe, and often exceed those seen with other pituitary tumors of similar or larger size. A cephalgic property may be inherent in excess GH or some other substance cosecreted from somatotrope tumors, as is also suggested by the sudden and dramatic relief of headaches by administration of somatostatin or its analogs (see later).
DIAGNOSTIC TESTING
In acromegaly, GH secretion remains pulsatile, with increased amplitude and failure to completely cease between pulses. Pulse frequency may also be increased. GH levels vary widely, both within and outside the normal range. Therefore, a random GH level is not diagnostic of acromegaly, just as it cannot be diagnostic of hypopituitarism. The mixture of GH molecular variants secreted in acromegaly does not differ from the mixture secreted normally. Dynamic testing of GH suppressibility is required for diagnosis.
The diagnosis of acromegaly has been facilitated by IGF-I measurement. An elevated serum IGF-I level is almost pathognomonic for acromegaly, as few other conditions cause high IGF-I levels. Furthermore, IGF-I is highly sensitive to even mild elevation of GH secretion. When acromegaly is suspected, serum IGF-I measurement should be performed as a screening test. This should then be followed by a standard oral glucose-tolerance test (75 or 100 g glucose). Glucose normally suppresses GH secretion, with plasma levels of <1 ng/mL within an hour or two of glucose administration. In acromegaly, GH levels are not normally suppressible and may even increase in response to glucose. Lack of suppression by glucose to <1 ng/mL is the definitive diagnostic test in the proper clinical setting suggesting acromegaly.
The severity of clinical manifestations is notoriously poorly correlated with serum GH levels; correlation with IGF-I levels may be better. IGF-I may be elevated, and clinical disease present, even at a mean GH level of 5 ng/mL.61 The hallmark of acromegaly, even in such mild cases, is the absence of cessation of GH secretion, which results in higher than normal interpulse nadirs and a lack of glucose-induced suppressibility of GH to <1 ng/mL. Frequently, patients with acromegaly have a paradoxical GH response to TRH or GnRH—findings that support the diagnosis but are not entirely specific. Measurements of IGFBPs or GHBP are not useful in the diagnosis of acromegaly. In the ectopic GHRH syndrome, peripheral serum GHRH levels are substantially elevated.52 However, this syndrome is so rare that routine screening is not recommended.
Pituitary imaging (MRI or computed tomographic scanning) frequently reveals a macroadenoma that may extend in any direction. Conventional radiography may show a ballooned sella turcica, the bony skull deformities described earlier, and enlarged sinuses.
TREATMENT
The goal of treatment is two-fold: complete eradication of the tumor and normalization of GH and IGF-I secretion. The criteria for cure have changed over the years, with progressive lowering of the GH threshold from 10 to 5 to 2 ng/mL. Cure rates quoted in the literature are correspondingly variable. Criteria for a true cure should be very stringent, with normal suppressibility of GH and serum IGF-I in the normal range. Many patients, although substantially improved with respect to clinical disease, do not achieve this criterion, but rather have low-grade, residual acromegaly.
The primary form of therapy is transsphenoidal adenomectomy. For microadenomas (<1 cm), the surgical cure rate in experienced hands ranges from 60% to 90%; for larger tumors it is from 35% to 71%.62,63 and 64 These numbers partly depend on the stringency of the criteria used to determine a cure. Early diagnosis is the key to a successful eradication of a small tumor. Selective removal of the adenoma should leave the rest of the pituitary intact, and postoperative hypopituitarism is uncommon. It cannot be emphasized enough that surgical outcomes depend on the experience and skill of the neurosurgeon; this procedure should be performed only in specialized centers. Radiation therapy is used for patients who are not cured by surgery alone. It can be delivered as conventional x-ray therapy, as proton beam therapy, or in the form of the gamma knife (multi-port, collimated cobalt-60 therapy). Radioactive pituitary implants have largely been abandoned. All three radiation modalities are attended by development of hypopituitarism. Moreover, they are slow in their onset of action, with conventional x-ray therapy requiring 5 to 10 years or more to lower GH levels to an acceptable range. Proton beam therapy acts faster but has been complicated by optic and oculomotor nerve damage and seizure disorders; its availability is limited to institutions that possess a cyclotron. Experience with gamma knife therapy is still limited; it is reserved for small tumors and, thus, is not well suited for those patients with macroadenomas who are most in need of radiation therapy.
Medical therapy is available in the form of dopamine agonists (bromocriptine, cabergoline) and somatostatin analogs (octreotide). These agents are largely reserved for patients with residual disease after surgery; they have generally not been used as primary therapy, although one study suggested that octreotide monotherapy may be considered for patients for whom a surgical cure is not anticipated.65 In contrast to their great efficacy in the treatment of prolactinomas, dopamine agonists are not very effective in acromegaly, either in lowering GH levels or in shrinking tumor size. High doses are needed, and patient acceptance is poor because of side effects. Octreotide, on the other hand, is quite effective; its main drawback is that it has to be given by injection three times a day. However, long-acting analogs (lanreotide) or formulations (octreotide LAR) have been developed and are effective when injected in 20- to 40-mg doses at biweekly or monthly intervals. Octreotide can have a marked, immediate effect in relieving headaches—a phenomenon that is poorly understood. Future medical therapy may include use of a GH antagonist that is presently in clinical trials. Antagonism at the GHR level is based on the disabling of binding site 2 in the GH molecule, thereby preventing productive GHR dimerization. Preliminary results show that this antagonist is very effective in blocking GH action in patients with residual acromegaly. The hope is that the combination of agents that decrease GH secretion with one that blocks GH action will finally meet the difficult challenge of treating patients who suffer from residual acromegaly despite the best efforts at optimizing surgical and radiologic therapy.
HYPERSENSITIVITY TO GROWTH HORMONE
GH hypersensitivity states have not been widely appreciated, but at least one such condition is very common: obesity. In obesity, IGF-I levels tend to be high or normal despite decreased GH secretion. GHBP levels are high, likely indicating increased GHR expression.13 This constellation is the opposite of that in malnutrition, which is associated with GH insensitivity. Obese children grow faster than lean children66—an old observation that was not understood until recently. Hyperinsulinemia was proposed as an explanation, but insulin does not promote linear growth. Other than enhanced growth, the pathophysiologic consequences of the GH hypersensitivity associated with obesity are not clear; further studies are required to determine whether it contributes to increased morbidity.
Considerable advances have been made in our understanding of the GHRH–GH–IGF axis during the past few years. The genetic control of pituitary development and somatotrope function has been partially elucidated, with human disease linked to several control factors, such as Rpx, Prop-1, Pit-1, GHRH-R, and Gsa. GH action has become far better understood through detailed molecular modeling of the GH-GHR interaction, the study of GHR mutations and their functional consequences, the partial elucidation of the GHR signaling cascade, and the assessment of GHR regulation through GHBP measurements in various physiopathologic conditions. GH therapy for adults with hypopituitarism has come of age, with several new insights gained about the importance of GH in maintaining normal body composition and metabolism during adult life.
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