Pituitary function and pathophysiology

Growth hormone–releasing hormone

The GHRH gene is located on chromosome 20q11.2. Prepro-GHRH is a polypeptide chain of 108 amino acids (12.4 kDa). Removal of the 20 amino acid signal (leader) sequence peptide yields the 88 amino acid pro-GHRH. Cleavage of the 11 amino acid N-terminal pro-sequence and the 31 amino acid C-terminal pro-sequence, with release of two free amino acids (positions 76 to 77 with reference to prepro-GHRH), produces the 44 amino acid mature GHRH. The terminal leucine of GHRH is amidated. Alternative splicing of the mRNA (isoform 2) produces a prepro-GHRH protein of 107 amino acids, which is missing amino acid 103.

Somatostatin

Somatostatin is also known as somatotropin release–inhibiting hormone (SRIH). It is widely expressed throughout the body (CNS, gut, and δ-cells of the islets of Langerhans) and produces multiple physiologic effects. Somatostatin receptors are likewise widely distributed (see Table 55.3 ). Somatostatin functioning as SRIH is produced by the PVN of the hypothalamus. In pancreatic islets, somatostatin suppresses both glucagon and insulin secretion, whereas somatostatin release is stimulated by both of these hormones. In this way, δ-cell somatostatin modulates islet function by smoothing out extremes in the secretion of glucagon and insulin to maintain a stable blood glucose concentration. Somatostatin in the gut is found in highest concentration in the duodenum and jejunum.

The somatostatin gene is located on chromosome 3q2. Expression of the somatostatin gene produces the 116 amino acid polypeptide prepro-somatostatin. Cleavage of the signal sequence (24 amino acids) produces pro-somatostatin (92 amino acids), and subsequent cleavage of the N-terminal pro-sequence (64 amino acids) yields a 28 amino acid form of somatostatin (SST-28). SST-28 has an intrachain disulfide bond between amino acids 17 and 28. In many tissues, SST-28 undergoes cleavage to a 14 amino acid form (SST-14) through removal of the N-terminal 14 amino acid sequence by the enzymes prohormone convertase 1/prohormone convertase 2 (PC1/PC2) and carboxypeptidase E (CPE). SST-14 is the major form of somatostatin in the CNS and δ-cells, whereas SST-28 is the major form in the gastrointestinal tract. SST-28 is also the major circulating form of somatostatin. Therefore somatostatin measurements in peripheral blood do not reflect SRIH secretion. Somatostatin is highly conserved in nature; all vertebrates have the identical sequence for SST-14.

In addition to GH suppression, somatostatin also suppresses TRH, TSH, CRH, and ACTH. However, the effect of somatostatin on the regulation of the adrenal cortical and thyroid axes is usually minor. In the gastrointestinal tract, somatostatin reduces the secretion of multiple hormones, including (1) gastrin, (2) secretin, (3) cholecystokinin, (4) vasoactive intestinal polypeptide, (5) motilin, (6) neurotensin, and (7) pepsin, and reduces gastric pH, intestinal motility, ion and nutrient absorption, and proliferation of the mucosa (see Chapter 52 ). This motivates the clinical use of octreotide (a synthetic somatostatin analogue) in the medical management of VIPoma and glucagonoma. Calcitonin, catecholamines, renin, and pancreatic exocrine function and insulin release are also suppressed by somatostatin. Indium-111 and gallium-68 labeled octreotide have been used for imaging, and lutetium-177 labeled octreotide has been used in radiotherapy of tumors expressing somatostatin receptors (e.g., neuroendocrine tumors). For more information on neuroendocrine tumors, refer to Chapter 53 .

Growth hormone–releasing hormone receptor

The anterior pituitary somatotroph GHRH receptor (GHRHR) is a member of family B-III of the G-coupled receptor superfamily (the “secretin” family). Receptors for (1) secretin, (2) vasoactive intestinal polypeptide, (3) parathyroid hormone (PTH), and (4) calcitonin share partial sequence identity with GHRHR.

Pre-GHRHR is a 423-amino-acid polypeptide that is converted to the mature 401-amino-acid form of GHRHR by removal of the 22-amino-acid signal peptide. The N-terminal extracellular domain is 110 amino acids. GHRHR has seven transmembrane domains and a 42-amino-acid cytoplasmic domain. Amino acid 50 may be glycosylated.

Somatostatin release–inhibiting hormone receptor

Throughout the body, there are five receptors for somatostatin (SSTR1 through SSTR5; Table 55.3 ). Each receptor is encoded by a gene located on a separate chromosome. SSTR2 has two alternatively spliced isoforms. All of the SSTR receptors have seven transmembrane domains and are coupled with a pertussis toxin–sensitive G-protein. SSTR2, SSTR3, SSTR4, and SSTR5 are expressed in the pituitary.

Growth hormone

Growth hormone has two disulfide bridges (amino acids 54 and 165, and amino acids 182 and 189). Structurally, GH has four main α-helices, and within the connecting loops, it has three mini-helices. Two circulating forms of GH are present: a 22-kDa form that is a 191 amino acid chain (full-length GH) that represents 85 to 90% of circulating GH, and a 20-kDa GH that lacks amino acids 32 through 46. The 20-kDa form of GH results from alternative splicing of the GH mRNA transcript. In addition to the 22- and 20-kDa forms, circulating GH exists as aggregates and oligomers. “Big GH” is a dimer of GH monomers, and “big, big GH” is GH associated with its binding protein (GHBP). GHBP is the external domain of the GH receptor (GHR), which binds GH with high affinity and is produced by cleavage of the GHR. Approximately 55% of all circulating GH forms are monomeric; big GH and big, big GH represent approximately 27% and approximately 18% of circulating GH, respectively. Approximately 50% of GH is not bound to GHBP; approximately 45% is bound to GHBP, and the remaining 5% of GH is bound to low-affinity binding proteins. Considering the multiple forms of GH, it is not surprising that significant analytical biases were historically observed between different immunoassays for GH. With the availability of recombinant standardized reference materials, this problem is expected to improve.

The gene for GH (chromosome 17q24.2) is a member of the GH subfamily that includes (−5′ to 3′ direction) (1) GH (the GH1 gene), (2) a chorionic somatomammotropin (hPL) pseudogene designated CSHP, (3) a chorionic somatomammotropin-A designated CSH1, (4) the placentally produced 22-kDa GH variant (GH-V; gene designation GH2), and (5) chorionic somatomammotropin-B (gene designation CSH2). Somatomammotropin (hPL) is a placental hormone with growth-promoting properties. Prolactin (199 amino acids) shares a homologous amino acid sequence with GH, but prolactin, encoded on chromosome 6p22, is not part of the GH complex on 17q24.2.

GH has both direct and indirect activity. Its direct actions will be described in the following sections. The indirect activity of GH is mediated by IGF-I. To initiate its direct and indirect activity, GH binds to receptors (GHR) that appear to be expressed by all tissues.

Growth hormone receptor

The GHR is a member of the class 1 hematopoietic cytokine family. Other members of this family include receptors for erythropoietin, granulocyte-macrophage colony-stimulating factor, and various interferons. Structurally, the GHR is a single-chain, 620-amino-acid protein (130 kDa). Pre-GHR includes an 18 amino acid leader sequence. The GHR structure includes an extracellular domain (246 amino acids), a transmembrane domain (24 amino acids), and a cytoplasmic domain (350 amino acids). When the extracellular portion of the GHR is shed, the 55-kDa GHBP moiety is released into the circulation.

Four isoforms of the GHR are expressed by alternative splicing of the nascent mRNA. Isoform 1 is the full-length receptor. Isoform 2 differs in the sequence of amino acids 292 to 297 (with reference to pre-GHR) and lacks amino acids 298 to 638. Isoform 3 differs in the sequence of amino acids 292 to 294 and lacks amino acids 295 to 638. An alanine at position four is replaced by aspartic acid, and amino acids 25 to 46 are missing in isoform 4.

The GHR exists as a cell surface dimer in its inactive state ( Fig. 55.3 ). When GH binds to the GHR, the receptor recruits or activates 120-kDa Janus-associated kinase enzymes (JAK2; a type of adapter tyrosine kinase). JAK2 then exerts tyrosine kinase activity by phosphorylating itself and the GHR. ^, Phosphorylation activates JAK2, which triggers several intracellular pathways involving (1) signal transducers and activators of transcription (STATs), (2) the insulin receptor substrate, (3) phosphatidylinositol 3′-kinase (PI3K), and (4) a mitogen-activated protein kinase (MAPK). Via receptor-associated kinases, members of the STAT family are phosphorylated to permit the formation of homodimers or heterodimers that act as transcriptional activators once they translocate to the cell nucleus. STAT5b is involved, but it is unclear whether STAT5a is also involved. In its role as a transcription factor, phosphorylated, dimerized STAT5b enters the nucleus to promote gene transcription. Independent of JAK2, GHR signaling can be effected via Src , which is a tyrosine kinase. (Note: Src is the Rous sarcoma virus protooncogene).

Insulin-like growth factors

IGF-I is a member of the insulin-related peptide family whose other members include IGF-II, insulin, and relaxin. Stimulated by hCG during pregnancy, relaxin is produced by the corpus luteum verum (the corpus luteum of pregnancy), the decidua (the uterine lining during pregnancy), and the placenta. Relaxin increases collagenase activity to soften and lengthen the cervix and pubic symphysis and facilitate parturition. Relaxin also reduces uterine contractility by inhibiting myosin kinase activity. In humans, there are three nonallelic relaxin genes: RLN1, RLN2, and RLN3.

Proinsulin, IGF-I, IGF-II, and relaxin are all composed of two domains (A and B) joined by a connecting domain. The connecting domains vary in sequence and length much more than the A and B domains. The connecting domain of proinsulin is cleaved to release C-peptide (connecting peptide), producing insulin A and B chains. Insulin, IGF-I, IGF-II, and relaxin have two disulfide bridges. IGF-I and IGF-II share 62% homology, and they each share 50% homology with insulin.

The 110 amino acid sequence of preproinsulin includes a signal peptide (amino acids 1 to 24), the insulin B chain (amino acids 25 to 54), C-peptide (amino acids 57 to 87), and the insulin A chain (amino acids 90 to 110). The two interchain disulfide bonds are between amino acids 31 and 96, and 43 and 109. The single intrachain disulfide bond is between amino acids 95 and 100.

Two forms of prepro–IGF-I are expressed as a consequence of alternative mRNA splicing: IGF-IA and IGF-IB. The IGF-IA preprohormone is 153 amino acids, including a signal peptide (amino acids 1 to 21), an N-terminal propeptide (amino acids 22 to 48), IGF-I (70 amino acids), and a C-terminal propeptide (the E domain, amino acids 119 to 153). The IGF-I polypeptide includes the B domain (amino acids 49 to 77), the C (connecting) domain (amino acids 78 to 89), the A domain (amino acids 90 to 110), and the D domain (amino acids 111 to 118). Three disulfide bonds are present between amino acids 54 and 96, 66, and 109, and 95 and 100. IGF-I is not glycosylated. A relatively common (∼0.6%) single nucleotide polymorphism in IGF-I (A70T) has been identified in the screening population for acromegaly which is clinically relevant since some commercial immunoassays do not detect this variant form leading to factitiously decreased IGF-I concentrations.

The 195 amino acid IGF-IB preprohormone is composed of a signal peptide (amino acids 1 to 21), a propeptide (amino acids 22 to 48), IGF-I (70 amino acids), and another propeptide region (the E domain, amino acids 119 to 195). Differences in the D domain of the prepro–IGF-I distinguish IGF-IA from IGF-IB; the tertiary structure of the IGF-I proteins and the placement of disulfide bonds are identical between IGF-IA and IGF-IB.

The IGF-II preprohormone comprises 180 amino acids. The first 24 residues constitute the signal peptide. After their removal, IGF-II is derived from pro–IGF-II after cleavage of the C-terminal E peptide (amino acids 92 to 180). Therefore amino acids 25 to 91 include the B region (amino acids 25 to 52), the C region (amino acids 53 to 64), the A region (amino acids 65 to 85), and the D region (amino acids 86 to 91) of IGF-II. Isoform I is the full-length prepro–IGF-II (180 amino acids). Formed by alternative splicing, isoform II lacks amino acid 25 (alanine) and is therefore 179 amino acids in length. IGF-II is glycosylated at amino acid 99 and has three intrachain disulfide bonds between amino acids 33 and 71, 45 and 84, and 70 and 75. A potential glycosylation site is amino acid 163.

Prorelaxin is a 185-amino-acid protein that contains a signal sequence (amino acids 1 to 22), a B chain (amino acids 23 to 53), a connecting propeptide (amino acids 56 to 158), and an A chain (amino acids 163 to 185). A–B interchain disulfide bonds can occur between amino acids 35 and 172, and 47 and 185. An additional disulfide bridge may occur between amino acids 171 and 176.

IGF-I and IGF-II circulate together with an IGF binding protein (IGFBP) (most importantly IGFBP-3), and the acid-labile subunit (ALS) to form a 150-kDa trimeric protein complex. Approximately 75 to 80% of IGF-I/IGFBP-3 complexes are trimeric; the remaining IGF-I/IGFBP-3 complexes are dimeric and may include other IGFBPs. Less than 1% of the total IGF-I is free (the biologically active form). The binding affinity of IGF-I for the insulin receptor is low (≈7% of insulin affinity) but circulating IGF-I concentrations exceed insulin by three orders of magnitude. Without binding proteins, therefore IGF-I could cause potentially devastating hypoglycemia.

The trimeric IGF-I-IGFBP-3-ALS complexes do not normally cross capillary membranes because of their size. However, the 50-kDa binary complex and free IGF-I are able to enter the interstitium, where binding to type I IGF receptors can occur.

Most of the circulating IGF-I is produced by hepatocytes. However, IGF-I is also produced locally throughout the body and thus acts as a paracrine and an autocrine hormone. The possible endocrine (systemic) influence of IGF-I on growth is discussed later.

Similar to IGF-I, IGF-II does not normally produce hypoglycemia. However, tumors that secrete a larger than normal form of IGF-II have been described. These are usually more than 0.5 kg in size; nonislet cell tumors are most often of mesenchymal or hepatic origin. Since big IGF-II does not bind normally to IGFBP-3, the free IGF-II concentration is greatly elevated, and the molar IGF-II to IGF-I ratio is greater than 10. As a result of IGF-II binding to the insulin receptor, the clinical syndrome is similar to that of hypoglycemia caused by hyperinsulinism (i.e., absence of ketonemia with no elevation of free fatty acids, lactate, or alanine), and insulin itself is suppressed because β-cells are normal. Physiologically, hypoglycemia stimulates the release of counter-regulatory hormones such as GH, but in this scenario IGF-II suppresses the GH axis. Removal of the tumor leads to the resolution of hypoglycemia. ^,

Insulin-like growth factor binding proteins

Because of their high affinity (K _d 10 ⁻¹⁰ to 10 ⁻¹¹ M) for IGFs, IGFBPs are regarded as inhibitors of IGF action. IGFBPs have higher affinity for IGFs than do the IGF receptors. IGFBP-3 has biological actions independent of the IGF/IGF-I receptor axis. Receptors for IGFBPs have been described. Proteolysis of IGFBPs releases IGF-I; therefore IGFBP proteases can influence free IGF-I concentrations. Table 55.4 summarizes the features of the seven known IGFBPs. From a clinical standpoint, only IGFBP-3 has relevance as it is used as an adjunctive tool in addition to GH and IGF-I in the diagnosis of GH deficiency.

Receptors for insulin-like growth factors

Two types of receptors for IGFs have been identified: the type I IGF receptor and the type II IGF receptor ( Fig. 55.4 ). Structurally, the type I IGF receptor is similar to the insulin receptor. Because this receptor does not exclusively bind IGF-I, the terminology “IGF-I receptor” is not recommended. The type I receptor is derived from a single precursor protein of 1367 amino acids that include the 30 amino acid signal peptide. The 706 amino acid (130 kDa) α-chain is extracellular and is bound by a disulfide bond to the transmembrane 90-kDa (627 amino acids) β- chain. Cleavage of the α- and β-chains releases a tetrapeptide (707 to 710: arginine-lysine-arginine-arginine). Beta-chain amino acids 906 to 929 form a transmembrane domain. The receptor exists as a homodimer (β-α-α-β) with the two α-chains bound to each other by two disulfide bonds. Similar to the type I IGF receptor, the insulin receptor is a homodimer of two 135-kDa α-chains and two 95-kDa β-chains.

Tyrosine kinase activity in the cytoplasmic portion of the type I IGF receptor β-chain results from binding of an IGF molecule to the cysteine-rich portion of the α-chains (amino acids 148 to 302), which causes conformational changes in both α- and β-chains. Intracellular signaling involves autophosphorylation and phosphorylation of the 185-kDa insulin receptor substrate 1, which is the predominant target of the active type I IGF receptor. The type I IGF receptor binds IGF-I with higher affinity than IGF-II, and affinity for insulin is lower than the affinity of the receptor for IGF-I or IGF-II. The affinities of the insulin receptor are the opposite: insulin ⪢ IGF-II > IGF-I.

The type II IGF receptor is structurally dissimilar from the type I IGF receptor and the insulin receptor. The 270-kDa, 2451-amino-acid, type II IGF receptor is a monomeric protein that is similar to the epidermal growth factor (EGF) receptor. (Note: The leader sequence is 40 amino acids.) The EGF receptor itself is also known as ErbB1 or HER1. The external portion of the receptor is 2264 amino acids, the transmembrane domain is 23 amino acids, and the cytoplasmic domain is 164 amino acids. Beginning at the N terminus, there are 13 amino acid repeats of approximately 150 amino acids, and a 47 amino acid fibronectin type II domain, followed by 2 more repeats. Evidence indicates at least five glycosylation sites: amino acids 112 (with preference for the pre–type II IGF receptor), 581, 626, 747, and 1246. Two disulfide bonds are found between amino acids 1903 and 1927 and between amino acids 1917 and 1942.

Ligand binding to EGF receptors results in dimerization and tyrosine kinase activation. The external ligand-binding domain of EGFs is composed of numerous short amino acid repeats. The type II IGF receptor removes IGF-II from the circulation. The type II IGF receptor binds mannose-6-phosphate, in addition to IGFs, permitting the uptake and intracellular movement of mannose-6-phosphate–containing lysosomal enzymes. The binding sites for IGFs and mannose-6-phosphate are found on different parts of the receptor. The affinities of the type II IGF receptor are as follows: IGF-II ⪢ IGF-I > insulin. Because this receptor does not exclusively bind IGF-II, the terminology “IGF-II receptor” is not recommended.

A hybrid receptor consisting of the α–β-chain of the insulin receptor and the α–β-chain of the type I IGF receptor has been described. It has been suggested that these hybrid receptors may allow cancers to respond to insulin. In cancers, insulin is also thought to act through the insulin signaling pathway via insulin receptors and also probably acts through receptors that bind IGF-I. Thus IGF-I also plays a role in cancer biology. Increasing evidence suggests that IGF-I may enhance the growth of many tumors, and it is known that acromegaly confers increased risk for both colorectal and thyroid cancer. Thus the casual use of IGF-I injections in children to enhance growth in short but otherwise normal children is problematic and potentially carcinogenic.

Physiologic actions

Growth hormone effects can be classified as indirect or direct. GH directly raises blood glucose by stimulating gluconeogenesis and reducing insulin sensitivity. Also, it causes adipose tissue lipolysis, and the resulting GH-induced elevations in free fatty acids provide an alternative energy source that serves to spare glucose for CNS use. Therefore when glucose and free fatty acid concentrations are raised at times of stress, in partnership with epinephrine, glucagon, and cortisol, fuels for the fight-or-flight response are provided. GH has other effects on intermediary metabolism: GH stimulates the uptake of nonesterified fatty acids by muscle and accelerates the mobilization and metabolism of fat from adipose tissue to the liver.

At the epiphysis of growing bone, GH promotes epiphyseal prechondrocyte differentiation. GH directly stimulates the production of the ternary complex of IGF-I, IGFBP-3, and the ALS. In turn, after entering the interstitium, unbound IGF-I binds to type I IGF receptors.

Indirect effects of GH are mediated through IGF-I production, which (together with GH) is necessary for linear growth in childhood. IGF-I is mitogenic and antiapoptotic. Epiphyseal prechondrocyte differentiation stimulated by GH, along with the local effects of IGF-I (also under the control of GH), stimulates the clonal expansion of differentiating chondrocytes.

Thus the overall effect of GH is to promote growth in soft tissue, cartilage, and bone. This action results from stimulation of protein synthesis that is induced in part by an increase in amino acid transport through cell membranes. The effects of GH on bone and muscle are exerted both directly and through the effects of IGF-I under the influence of GH. Increased growth of soft tissue and the skeleton is accompanied by changes in electrolyte metabolism, including positive nitrogen and phosphorous balance, a rise in plasma phosphorous concentration, and a fall in blood urea and amino acid concentrations. Additional responses to GH include increased intestinal absorption of calcium and decreased urinary excretion of sodium and potassium. The metabolic changes most likely are caused by increased uptake of these ions by growing tissue.

IGF-I increases glucose oxidation in adipose tissue and stimulates glucose and amino acid transport into diaphragmatic muscle and heart muscle. Synthesis of collagen and proteoglycans is enhanced by IGF-I, which also has positive effects on calcium, magnesium, and potassium homeostasis. The insulin-like effects of this growth factor have been ascribed in part to its structural similarity to insulin.

Evidence indicates that the local effects of IGF-I (autocrine or paracrine) are predominant in stimulating growth when compared with the systemic effects of IGF-I produced by the liver. When the hepatic IGF-I gene was knocked out in mice (although nonhepatic tissues expressed IGF-I), growth was normal, and IGFBP-3 and ALS concentrations were low. IGF-II may function as a growth factor in utero; however, its secretion in utero is not under the control of GH.

In the absence of GH, IGF-I is not as effective a growth stimulant as it is when GH and IGF-I both are present. IGF-I treatment alone is not recommended as therapy for GH deficiency; IGF-I therapy is reserved for cases of GH resistance due to GHR deficiency (e.g., Laron syndrome). ^,

GH (through IGF-I) and insulin induce growth in a similar manner because both have protein anabolic effects and stimulate the transport of amino acids into peripheral cells. Their respective effects on glucose homeostasis, however, oppose one another—chronic GH excess induces diabetes mellitus. Most growth-promoting GH effects are delayed rather than immediate and are exerted primarily through IGF-I.

IGF-I concentrations vary widely with age and gender. IGF-I rises during childhood, and during puberty, IGF-I concentrations can be two to three times the adult concentration. After adolescence, IGF-I concentrations show steep decline until age 30, followed by a gradual decline until old age.

GH is not the only determinant of IGF-I concentration in the circulation. Transformation of the GH stimulus to IGF-I production and secretion is modulated by (1) nutrition, (2) the presence or absence of chronic inflammation, (3) thyroid function, (4) glucocorticoids, and (5) sex steroids. IGF-I secretion is reduced by (1) malnutrition, (2) malabsorption (e.g. inflammatory bowel disease, celiac disease), (3) obesity (4) cystic fibrosis, (5) chronic disease, (6) sex hormone deficiency in adolescence. Therefore a decreased IGF-I concentration is not necessarily synonymous with GH deficiency.

In cases of acquired GH resistance and genetic GH resistance (GHR mutation or signaling disorder), GH concentrations will rise, and high concentrations of GH produce hyperlipidemia and hyperglycemia. Cases of acquired GH resistance are not treated with GH or IGF-I, but instead are treated by addressing the underlying disorder.

The actions and regulation of IGF-II have been debated. IGF-II is believed to be important for intrauterine growth. Mice display intrauterine growth retardation when the IGF-II gene is knocked out. Although IGF-II–producing tumors are rare, such tumors can produce hypoglycemia attributable to incompletely processed variant of IGF-II. ^, Both IGF-I and IGF-II are of great interest to oncology researchers; the reader is referred to the literature for a detailed discussion of this topic.

Clinical significance

Diagnosis of clinically important states of GH excess or deficiency are uncommon and may go unrecognized for years. GH concentrations vary widely under normal circumstances; therefore random measurements of GH, in general, are not diagnostically useful. A single GH measurement cannot distinguish between normal fluctuations and the low or high concentrations that are typical of various diseases. GH measurements are best determined as part of dynamic function testing: physiologic or pharmacologic provocative stimuli are used to help diagnose GH deficiency, whereas GH suppression (or lack thereof) following glucose administration is used to identify GH excess. IGF-I concentrations often correlate better with the clinical severity of acromegaly than with glucose-suppressed or basal GH concentrations.

In contrast to GH, a single measurement of IGF-I is considered to be an accurate reflection of GH-IGF-I production, irrespective of the time of the day or meals. IGF-I has a much longer half-life than GH and accordingly has more stable plasma concentrations. The half-life of GH is slightly longer than 15 minutes, whereas the half-life of the trimeric IGF-I-IGFBP-3-ALS complex is 17 to 22 hours. The half-life of unbound IGF-I is only 10 to 20 minutes, but the unbound form of the hormone accounts for less than 1% of the total concentration. Serum concentrations of IGF-I are influenced by (1) age, (2) sex, (3) degree of sexual maturity, (4) thyroid status, (5) nutritional status, and (6) body mass index. As mentioned previously, IGF-I concentrations are low in GH deficiency and in patients with acute or chronic protein or caloric deprivation and, in the other extreme, obesity. In pediatric endocrinology, measurements of IGFBP-3 have been used in addition to IGF-I measurements to assess GH; however, the additional value of IGFBP-3 measurement over and above IGF-I measurement has not been firmly established. The diagnostic use of GH to stimulate IGF-I production is controversial and is not currently included in standard medical practice.

Growth hormone excess

Acromegaly is the rare clinical syndrome in adults resulting from GH excess. ^, Even less common is pituitary gigantism, which results from GH excess in childhood. The clinical features of acromegaly involve overgrowth of the skeleton and soft tissue, producing (1) acral enlargement (enlargement of the extremities), (2) organomegaly (enlarged heart and/or liver), (3) facial coarsening, (4) intestinal polyposis and attendant increased risk of colorectal cancer, (5) premature cardiovascular disease, (6) hyperhidrosis (increased sweating), (7) skin tags, (8) bone and joint disorders, (9) myopathy with weakness, (10) insulin resistance, and often (11) diabetes mellitus. Premature cardiovascular disease is the most common cause of death in individuals with acromegaly. Gigantism is characterized by extreme tall stature, in addition to the clinical features of acromegaly, as pathologic GH excess occurs before epiphyseal fusion is complete (e.g., in children or adolescents).

Most cases of acromegaly (≈95%) result from anterior pituitary GH-secreting tumors (“somatotroph adenomas” or “somatotropinomas”). Somatotropinomas are usually macroadenomas (>10 mm in diameter) by the time they come to clinical attention; the vast majority of these can be visualized by computed tomography (CT) or MRI. Some anterior pituitary tumors secrete both GH and prolactin (somatomammotropinomas). GH-secreting anterior pituitary adenocarcinomas are exceedingly rare. Approximately 5% of GH-secreting tumors are familial and caused by disorders such as multiple endocrine neoplasia type 1 syndrome, familial acromegaly, Carney syndrome, McCune-Albright syndrome, and familial isolated pituitary adenoma. Rare causes of acromegaly include GHRH-secreting hypothalamic tumors, extrapituitary somatotropinomas, and GHRH-secreting islet cell tumors, or those of lung or breast.

In severe or advanced cases of GH excess, the diagnosis may be nearly certain on the basis of physical appearance alone. However, in less severe or early cases, the physical changes may be subtle and gradual, so careful attention to clinical findings is required to make an early diagnosis. The reversibility of tissue changes depends largely on the duration of the disease. In addition to soft tissue changes, acromegaly may cause severe disability or death from cardiac, pulmonary, and/or neurologic sequelae. The most important requirement for the diagnosis of acromegaly is the demonstration of inappropriate and excessive GH secretion.

As many as 10% of patients with active acromegaly have random serum GH concentrations that fall within the reference interval. Essentially all patients with acromegaly have an abnormal GH response to an oral glucose load (see Box 55.1 ). Patients with acromegaly typically show modest or no change in their basal concentration of GH or demonstrate a paradoxical increase in GH ; in contrast, normal individuals show suppression of GH concentrations to less than 0.4 ng/mL (0.4 μg/L) after a 75-g oral glucose. ^, IGF-I is considered to be the most important diagnostic tests for the initial diagnosis of acromegaly. ^, Additionally, because of the development of GH-receptor antagonist therapies for acromegaly (e.g. pegvisomant), IGF-I is also the only clinical tool available for monitoring patients receiving these therapies.

Growth hormone deficiency and growth retardation

In children, short stature with a normal growth velocity (≥4 to 5 cm/year) results from (1) familial short stature, (2) primordial growth failure (prenatal-onset growth failure), or (3) constitutional delay in growth and adolescence (delayed maturation). Short stature with a low growth velocity (<4 to 5 cm/year) results from genetic short stature, chronic illness, malnutrition, deprivation (nutritional or psychological), Turner syndrome, or endocrine disorders (e.g., hypothyroidism, disorders of the GHRH-GH-IGF-I axis, extremely poorly controlled diabetes, rickets, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, and Cushing syndrome).

Idiopathic short stature is the term that is used when children with short stature and a low growth velocity lack evidence of pathology. It has been increasingly recognized that 5 to 15% of these children have a mutation in the SHOX (short stature homeobox) gene located on chromosome Xp22.33. Forearm anomalies are common in such children, and they become more evident during puberty.

GH deficiency is not a common cause of growth retardation. Approximately one-half of children evaluated for growth retardation have no specific organic cause; approximately 15% have an endocrine disorder, of which approximately half (approximately 8% of all children with short stature) have GH deficiency. Children with significantly reduced height and low growth velocities with no clear explanation should be screened for GH deficiency once other endocrine disorders have been excluded.

GH deficiency in children is characterized by (1) short stature, (2) low growth velocity, (3) immature facial appearance, (4) delayed bone age on radiologic examination, and (5) increased adiposity. In cases of congenital GH deficiency, size at birth is usually normal because in utero IGF-I does not appear to be under GH control. Micropenis is evident in some boys with congenital GH deficiency and will resolve with GH replacement in childhood. Micropenis suggests hypopituitarism, although there are other causes for micropenis. Adults with GH deficiency experience (1) reduced muscle mass (“sarcopenia”), (2) increased central adiposity, (3) osteoporosis with decreased bone density, (4) increased fracture risk, (5) decreased quality of life, (6) dyslipidemia, and (7) increased risk of cardiovascular disease. GH deficiency is probably the most common endocrine abnormality in adults with large (non-somatotroph) pituitary adenomas and in patients who have undergone pituitary irradiation. Recovery of normal hormonal production after surgery for these types of pituitary adenomas occurs uncommonly. GH replacement therapy forms an important part of the clinical care of GH-deficient children. Whether GH therapy is required in GH-deficient adults remains controversial.

GH insufficiency can be a consequence of (1) hypothalamic disease, (2) disruption of the portal system between hypothalamic nuclei and the anterior pituitary, (3) GHRHR loss-of-function mutations, or (4) somatotroph disease. GH deficiency can occur in isolation (isolated GH deficiency) or together with other pituitary deficiencies (multiple pituitary hormone deficiencies [MPHDs] or combined pituitary hormone deficiencies [CPHD]). Patients with isolated GH deficiency should be followed clinically for the development of other pituitary hormone deficiencies because MPHD can evolve over time. Biochemical stimulation testing is necessary to establish the diagnosis of GH deficiency, GH resistance, or MPHD. In most affected children, the cause of GH deficiency is unknown (idiopathic GH deficiency). An organic cause is identified in about one in four children with proven GH deficiency; half of these children will be diagnosed with a CNS tumor.

Any type of hypothalamic disease or dysfunction can lead to or be associated with GHRH deficiency, including (1) tumors, (2) inflammation, (3) previous infection, (4) trauma (including previous surgery), (5) hemorrhage, (6) irradiation, and (7) malformations (e.g., SOD). Low-dose irradiation of the hypothalamus and/or pituitary can cause idiopathic GH deficiency, whereas higher doses of irradiation can cause MPHD. SOD is defined by the triad of (1) midline brain defects, such as agenesis of the septum pellucidum and/or corpus callosum, (2) hypoplasia of the optic nerve, and (3) anterior and/or posterior pituitary hormone abnormalities. A small number of cases of SOD are explained by mutations in HESX1, SOX2, and SOX3, all of which are transcription factors. HEXS1 (chromosome 3p14.3) is a paired-like homeobox gene, SOX2 (chromosome 3q26.3) is the SRY (sex-determining region on the Y chromosome) box 2 gene, and SOX3 (chromosome Xq27.1) is the SRY box 3 gene. Midline brain tumors, such as craniopharyngiomas, meningiomas, gliomas, germinomas, third ventricle colloid cysts, ependymomas, and optic nerve gliomas, also affect the hypothalamus. Disruptions in the hypothalamic-pituitary portal system can result from tumors, inflammation, previous infection, trauma (including previous surgery), and irradiation.

Congenital GH deficiency from pituitary disease has many causes, including GHRHR gene mutations (idiopathic GH deficiency type IB), GH1 mutations (idiopathic GH deficiency types IA, IB, II, and III, and bioinactive GH), and transcription factor mutations (which usually cause MPHD: LHX3, LHX4, PROP1, Pit-1, RIEG) and malformations (anencephaly and holoprosencephaly) ( Table 55.5 ). Homozygous LHX3 mutations have caused panhypopituitarism, with the exception that ACTH was not affected. Heterozygous LHX4 mutations have caused deficiencies of GH, TSH, and ACTH. PROP1 (name derived from PROphet of Pit-1; POU1F1; Pit-1 stands for “paired-like homeodomain transcription factor”) mutations cause deficiencies of GH, prolactin, TSH, and gonadotropins. ACTH deficiency has also occurred in some cohorts. PROP1 gene mutations are inherited as autosomal recessive traits. Pit-1 gene mutations cause GH, prolactin, and variable degrees of TSH deficiencies. These transcription factor mutations may be inherited as autosomal recessive or dominant traits. Heterozygous RIEG gene mutations (PITX2 , a paired-like homeobox gene) are the cause of Rieger syndrome, which may include GH deficiency. Features of Rieger syndrome encompass developmental abnormalities of the teeth, the anterior chamber of the eye, and the umbilicus. Mutations in GLI1, GLI2, Shh, ZIC2, SIX3, tgif, PATCHED1, DGF1, and FAST1 have variously been cited as causes of holoprosencephaly. Children with midline facial clefts (cleft lip, cleft palate, or combined) or a single central incisor can exhibit GH deficiency. A number of GH1 gene mutations have been identified to cause bioinactive GH. In these mutations, GH does not have full biological activity but may retain its immunoreactivity. Therefore in contrast to other forms of pituitary or hypothalamic disease, the measured GH concentration has been observed to be high. Reference laboratories can provide GHRHR , GH1 , and GHR gene sequencing services.

Acquired causes of pituitary disease include (1) tumors (anterior pituitary adenoma, craniopharyngioma), (2) congenital cysts (Rathke cleft cyst, arachnoid cyst), (3) infiltrative disease (amyloidosis, histiocytosis, hemochromatosis), (4) inflammation (autoimmune, granulomatous or IgG4-related hypophysitis), (5) infection, (6) trauma (including surgery), (7) bleeding, (8) irradiation, (9) infarction (from pituitary apoplexy and Sheehan syndrome). Hemochromatosis does not cause hypopituitarism until many decades have passed. Some investigators believe that all patients with “idiopathic” hypopituitarism should be screened for hemochromatosis.