GH and prolactin are structurally related members of the somatotropic hormone family and share many biological features, thus providing a rationale for discussing them together. The somatotropes and lactotropes, the pituitary cells that produce GH and prolactin, respectively, derive during pituitary development from a common precursor and are eosinophilic in histological sections. Consistent with their common origin, defects in certain transcription factors affect both cell lineages. In addition to their structural similarities, GH and prolactin act via membrane receptors that belong to the cytokine receptor family and modulate target cell function via very similar signal transduction pathways (Chapter 3). The secretion of both hormones is subject to strong inhibitory input from hypothalamic neurons; for prolactin, this negative dopaminergic input clearly is the predominant regulator of secretion. Finally, several drugs that are used to treat excessive secretion of these hormones are effective to varying degrees for both GH and prolactin.
Physiology of the Somatotropic Hormones
Structures of the Somatotropic Hormones. The gene encoding human GH resides on the long arm of chromosome 17 (17q22), which also contains three different variants of placental lactogen and a GH variant, chorionic somatotropin, expressed in the syncytiotrophoblast. GH is secreted by somatotropes as a heterogeneous mixture of peptides; the principal form is a single polypeptide chain of 22 kDa that has two disulfide bonds and is not glycosylated. Alternative splicing deletes residues 32 to 46 of the larger form to produce a smaller form (∼20 kDa) with equal bioactivity that makes up 5-10% of circulating GH. Recombinant human GH consists entirely of the 22 kDa form, which provides a way to detect GH abuse for sports performance enhancement.
Additional GH species, differing in size or charge, are found in serum, but their physiological significance is unclear. In the circulation, a 55 kDa protein binds approximately 45% of the 22 kDa and 25% of the 20 kDa forms; this binding protein contains the extracellular domain of the GH receptor and apparently arises from proteolytic cleavage. A second protein unrelated to the GH receptor also binds approximately 5-10% of circulating GH with lower affinity. Bound GH is cleared more slowly and has a biological t1/2 ∼10 times that of unbound GH, suggesting that the bound hormone may provide a GH reservoir that dampens acute fluctuations in GH levels associated with its pulsatile secretion. Alternatively, the binding protein may decrease GH bioactivity by preventing it from binding to its receptor in target tissues. Obesity increases circulating levels of GH binding proteins and thus may affect the clinical response to exogenous GH.
Human prolactin is a 23 kDa protein with three intramolecular disulfide bonds. It is synthesized by lactotropes, and a portion of the secreted hormone is glycosylated at a single Asn residue. In circulation, dimeric and polymeric forms of prolactin also are found, as are degradation products of 16 kDa and 18 kDa. As with GH, the biological significance of these different forms is not known.
Regulation of Secretion of the Somatotropic Hormones. Daily GH secretion varies throughout life; secretion is high in children, peaks during puberty, and then decreases in an age-related manner in adulthood. GH is secreted in discrete but irregular pulses. Between these pulses, circulating GH falls to levels that are undetectable with most assays. The amplitude of secretory pulses is greatest at night, and the most consistent period of GH secretion is shortly after the onset of deep sleep.
GH secretion, as illustrated in Figure 38–2, incorporates many of the classic features of endocrine regulation. GHRH, produced by hypothalamic neurons found predominantly in the arcuate nucleus, stimulates GH secretion by binding to a specific GPCR on somatotropes that resembles most closely the receptors for secretin, vasoactive intestinal polypeptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP), glucagon, glucagon-like peptide-1 (GLP-1), calcitonin, and parathyroid hormone (PTH). Upon binding GHRH, the GHRH receptor couples to Gs to raise intracellular levels of cyclic AMP and Ca2+, thereby stimulating GH synthesis and secretion. Loss-of-function mutations of the GHRH receptor cause a rare form of short stature in humans, thereby demonstrating its essential role in normal GH secretion (Wajnrajch et al., 1996).
Typical of endocrine systems, GH and its major peripheral effector, insulin-like growth factor 1 (IGF-1), act in negative feedback loops to suppress GH secretion. The negative effect of IGF-1 is predominantly through direct effects on the anterior pituitary gland. In contrast, the negative feedback action of GH is mediated in part by SST, which is synthesized in more widely distributed neurons.
Somatostatin is synthesized as a 92–amino acid precursor and processed by proteolytic cleavage to generate two peptides: SST-28 and SST-14. SST-14 consists of the carboxy-terminal 14 amino acids of SST-28, which form an intrapeptide disulfide bond (Figure 38–3). SST exerts its effects by binding to and activating a family of five related GPCRs that signal through Gi to inhibit cyclic AMP accumulation and to activate K+ channels and protein phosphotyrosine phosphatases.
Growth hormone secretion and actions. Two hypothalamic factors, growth hormone–releasing hormone (GHRH) and somatostatin (SST) stimulate or inhibit the release of growth hormone (GH) from the pituitary, respectively. Insulin-like growth factor-1 (IGF-1), a product of GH action on peripheral tissues, causes negative feedback inhibition of GH release by acting at the hypothalamus and the pituitary. The actions of GH can be direct or indirect (mediated by IGF-1). See text for discussion of the other agents that modulate GH secretion and of the effects of locally produced IGF-1. Inhibition, −; stimulation, +.
Structures of somatostatin-14 and selected synthetic analogs. The amino acid sequence of somatostatin (SST)-14 is shown. Residues that play key roles in receptor binding, as discussed in the text, are shown in red. Also shown are the structures of the two clinically available synthetic analogs of somatostatin, octreotide and lanreotide, and three other analogs that have been used in clinical trials, seglitide, vapreotide, and pasireotide. APro, [(2-aminoethyl) aminocarboxyl oxy]-L-proline; D-Nal, (3-(2-napthyl)-D-alanyl; PGly, phenylglycine; BTyr, benzyltyrosine.
Each of the SST receptor subtypes (abbreviated SSTRs) binds SST with nanomolar affinity; whereas receptor types 1-4 (SSTR1-4) bind the two SSTs with approximately equal affinity, type 5 (SSTR5) has a 10- to 15-fold greater affinity for SST-28. SSTR2 and SSTR5 are the most important for regulation of GH secretion, and recent studies suggest that these two SSTRs form functional heterodimers with distinctive signaling behavior (Grant et al., 2008). SST exerts direct effects on somatotropes in the pituitary and indirect effects mediated via GHRH neurons in the arcuate nucleus. As discussed later, SST analogs play a key role in the pharmacotherapy of syndromes of GH excess and certain cancers.
Ghrelin, a 28-amino acid peptide that is octanoylated at Ser3, also stimulates GH secretion. Ghrelin is synthesized predominantly in endocrine cells in the fundus of the stomach but also is produced at lower levels at a number of other sites. Both fasting and hypoglycemia stimulate circulating ghrelin levels.
Ghrelin acts primarily through a GPCR called the GH secretagogue receptor. Although the interaction of ghrelin with this receptor directly stimulates GH release by isolated somatotropes, the major action on GH secretion apparently is through actions on the GHRH neurons in the arcuate nucleus. Apart from its effects on GH secretion, ghrelin also stimulates appetite and increases food intake, apparently by central actions on NPY and agouti-related peptide neurons in the hypothalamus. Thus, ghrelin and its receptor act in a complex manner to integrate the functions of the GI tract, the hypothalamus, and the anterior pituitary (Ghigo et al., 2005). Peptide and nonpeptide agonists (termed GH secretagogues) and antagonists of the GH secretagogue receptor are undergoing evaluation as possible modulators of neuroendocrine function.
Several neurotransmitters, drugs, metabolites, and other stimuli modulate the release of GHRH and/or SST and thereby affect GH secretion. DA, 5-HT, and α2 adrenergic receptor agonists stimulate GH release, as do hypoglycemia, exercise, stress, emotional excitement, and ingestion of protein-rich meals. In contrast, β adrenergic receptor agonists, free fatty acids, IGF-1, and GH itself inhibit release, as does the administration of glucose to normal subjects in an oral glucose-tolerance test.
Many of the physiological factors that influence prolactin secretion also affect GH secretion. Thus sleep, stress, hypoglycemia, exercise, and estrogen increase the secretion of both hormones.
Prolactin is unique among the anterior pituitary hormones in that hypothalamic regulation of its secretion is predominantly inhibitory. The major regulator of prolactin secretion is DA, which is released by tuberoinfundibular neurons and interacts with the D2 receptor, a GPCR on lactotropes, to inhibit prolactin secretion (Figure 38–4). Recent reports have suggested that the D2 receptor and the SST2 receptor can form heterodimers (Baragli et al., 2007), which may have implications for therapy (see following discussion).
Prolactin secretion and actions. Prolactin is the only anterior pituitary hormone for which a unique stimulatory releasing factor has not been identified. Thyrotropin-releasing hormone (TRH), however, can stimulate prolactin release and dopamine can inhibit it. Suckling induces prolactin secretion, and prolactin affects lactation and reproductive functions but also has varied effects on many other tissues. Prolactin is not under feedback control by peripheral hormones.
A number of putative prolactin-releasing factors have been described, including TRH, VIP, prolactin-releasing peptide, and PACAP, but their physiological roles are unclear. Under certain pathological conditions, such as severe primary hypothyroidism, persistently elevated levels of TRH can induce hyperprolactinemia.
Unlike GH, which plays important roles throughout life in both sexes, prolactin acts predominantly in women, both during pregnancy and in the postpartum period in women who breast-feed. Serum prolactin levels remain low in men but are elevated somewhat in normal cycling females. During pregnancy, the maternal serum prolactin level starts to increase at 8 weeks of gestation, increases to peak levels of 250 ng/mL at term, and declines thereafter to prepregnancy levels unless the mother breast-feeds the infant. Suckling or breast manipulation in nursing mothers transmits signals from the breast to the hypothalamus via the spinal cord and the median forebrain bundle, which, in turn, stimulate circulating prolactin levels. Prolactin levels can rise 10- to 100-fold within 30 minutes of stimulation. This response is distinct from milk letdown, which is mediated by oxytocin release from the posterior pituitary gland. The suckling-induced prolactin secretion involves both decreased secretion of dopamine by tuberoinfundibular neurons and possibly increased release of factors that stimulate prolactin secretion. The suckling response becomes less pronounced after several months of breast-feeding, and prolactin concentrations eventually decline to prepregnancy levels.
Prolactin also is synthesized in lactotropes near the end of the luteal phase of the menstrual cycle and by decidual cells early in pregnancy; the latter source is responsible for the very high levels of prolactin in amniotic fluid during the first trimester of human pregnancy. The function of this prolactin and what regulates its expression are not known.
Molecular and Cellular Bases of Somatotropic Hormone Action. All of the effects of GH and prolactin result from their interactions with specific membrane receptors on target tissues (Figure 38–5). Both the GH and prolactin receptors are widely distributed cell surface receptors that belong to the cytokine receptor superfamily and thus share structural similarity with the receptors for leptin, erythropoietin, granulocyte-macrophage colony-stimulating factor, and several of the interleukins. Like other members of the cytokine receptor family, these receptors contain an extracellular hormone-binding domain, a single membrane-spanning region, and an intracellular domain that mediates signal transduction.
Mechanisms of growth hormone and prolactin action and of GH receptor antagonism. Left (A): The binding of GH to a homodimer of the growth hormone receptor (GHR) induces autophosphorylation of JAK2. JAK2 then phosphorylates cytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate gene expression. The structurally related prolactin receptor also is a ligand activated homodimer that recruits the JAK-STAT signaling pathway (see text for further details). The GHR also activates IRS-1, which may mediate the increased expression of glucose transporters on the plasma membrane. The diagram does not reflect the localization of the intracellular molecules, which presumably exist in multicomponent signaling complexes. JAK2, janus kinase 2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHC, Src homology containing. Right (B): Pegvisomant, a recombinant pegylated variant of human GH, contains amino acid substitutions that increase the affinity for one site of the GHR but do not activate its downstream signaling cascade. It thus interferes with GH signaling in target tissues.
The mature human GH receptor contains 620 amino acids, approximately 250 of which are extracellular, 24 of which are transmembrane, and ∼350 of which are cytoplasmic. It exists as a preformed homodimer that forms a ternary complex with one molecule of GH. The formation of the GH-GH receptor ternary complex is initiated by high-affinity interaction of GH with one monomer of the GH receptor dimer (mediated by GH site 1), followed by a second, lower affinity interaction of GH with the GH receptor mediated by GH site 2; these interactions induce a conformational change that activates downstream signaling. As discussed later, pegvisomant is a GH analog with amino acid substitutions that disrupt site 2; it binds the receptor and causes its internalization but cannot trigger the conformational change that stimulates downstream events in the signal transduction pathway. Amino acid–substituted versions of human prolactin that act as antagonists at the prolactin receptor are also under development (Goffin et al., 2006).
The ligand-occupied GH receptor dimer lacks inherent tyrosine kinase activity. Rather, it provides docking sites for two molecules of JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family. The juxtaposition of two JAK2 molecules leads to trans-phosphorylation and autoactivation of JAK2, with consequent tyrosine phosphorylation of cytoplasmic proteins that mediate downstream signaling events (Lanning and Carter-Su, 2006). These include STAT proteins (Signal Transducers and Activators of Transcription), Shc (an adapter protein that regulates the Ras/MAPK signaling pathway), and IRS-1 and IRS-2 (insulin-receptor substrate proteins that activate the PI3K pathway). One critical target of STAT5 is the gene encoding IGF-1 (Figure 38–5). The fine control of GH action also involves feedback regulatory events that subsequently turn off the GH signal. As part of its action, GH induces the expression of a family of SOCS (suppressor of cytokine signaling) proteins and a group of protein tyrosine phosphatases that, by different mechanisms, disrupt the communication of the activated GH receptor with JAK2 (Flores-Morales et al., 2006).
Some studies have shown that the GH receptor can translocate to the nucleus and act as a coregulator to activate transcription and cell proliferation (Swanson and Kopchick, 2007). The precise role of this signal transduction pathway in GH physiology and pathophysiology remains to be defined.
The effects of prolactin on target cells also result from interactions with a cytokine receptor that is widely distributed and signals through many of the same pathways as the GH receptor. Alternative splicing of the prolactin receptor gene on chromosome 5 gives rise to multiple forms of the receptor that are identical in the extracellular domain but differ in their cytoplasmic domains. In addition, soluble forms that correspond to the extracellular domain of the receptor are found in circulation. Unlike human GH and placental lactogen, which also bind to the prolactin receptor and thus are lactogenic, prolactin binds specifically to the prolactin receptor and has no somatotropic (GH-like) activity.
Physiological Effects of the Somatotropic Hormones. The most striking physiological effect of GH—and the basis for its name—is the stimulation of the longitudinal growth of bones (Giustina et al., 2008). GH also increases bone mineral density after the epiphyses have closed and longitudinal growth ceases. These effects of GH involve the differentiation of prechondrocytes to chondrocytes and stimulation of osteoclast and osteoblast proliferation. Other effects of GH include the stimulation of myoblast differentiation (in experimental animals) and increased muscle mass (in human subjects with GH deficiency), increased glomerular filtration rate, and stimulation of preadipocyte differentiation into adipocytes. GH has potent anti-insulin actions in both the liver and peripheral sites (e.g., adipocytes and muscle) that decrease glucose utilization and increase lipolysis. Finally, GH has been implicated in the development and function of the immune system.
Growth hormone acts directly on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesis, but its anabolic and growth-promoting effects are mediated indirectly through the induction of IGF-1. Although most circulating IGF-1 is made in the liver, IGF-1 produced locally in many tissues is critical for growth, as revealed by normal growth in mice that have a hepatocyte-specific inactivation of IGF-1. Circulating IGF-1 is associated with a family of binding proteins, designated the IGF-binding proteins (IGFBPs), that serve as transport proteins and also may mediate certain aspects of IGF-1 signaling. Most IGF-1 in circulation is bound to IGFBP-3 and another protein called the acid-labile subunit.
The essential role of IGF-1 in growth is evidenced by patients with loss-of-function mutations in both alleles of the IGF1 gene, whose severe intrauterine and postnatal growth retardation is unresponsive to GH but responsive to recombinant human IGF-1, and by the association of mutations in the IGF-1 receptor with intrauterine growth retardation (Walenkamp and Wit, 2008).
After its synthesis and release, IGF-1 interacts with receptors on the cell surface that mediate its biological activities. The type 1 IGF receptor is closely related to the insulin receptor and consists of a heterotetramer with intrinsic tyrosine kinase activity. This receptor is present in essentially all tissues and binds IGF-1 and the related growth factor, IGF-2, with high affinity; insulin also can activate the type 1 IGF receptor but with an affinity approximately two orders of magnitude less than that of the IGFs. The signal transduction pathway for the insulin receptor is described in detail in Chapter 43.
Unlike GH, prolactin does not induce the synthesis of a second hormone that then mediates many of its effects in an indirect manner. Rather, prolactin effects are limited to tissues that express the prolactin receptor, particularly the mammary gland. A number of hormones—including estrogens, progesterone, placental lactogen, and GH—stimulate development of the breast and prepare it for lactation. Prolactin, acting via prolactin receptors, plays an important role in inducing growth and differentiation of the ductal and lobuloalveolar epithelia and is essential for lactation. Target genes, by which prolactin induces mammary development, include those encoding milk proteins (e.g., caseins), genes important for intracellular structure (e.g., keratins), genes important for cell-cell communication (e.g., amphiregulin and Wnt4), and components of the extracellular matrix (e.g., laminin and collagen).
Prolactin receptors are present in many other sites, including the hypothalamus, liver, adrenal, testes, ovaries, prostate, and immune system, suggesting that prolactin may play multiple roles outside of the breast. The physiological effects of prolactin at these sites remain poorly characterized, and specific defects in their function that result from prolactin deficiency have not been defined.
Pathophysiology of the Somatotropic Hormones
Distinct endocrine disorders result from either excessive or deficient GH production. In contrast, prolactin predominantly impacts endocrine function when produced in excess.
Excess Production of Somatotropic Hormones. Syndromes of excess secretion of GH and prolactin typically are caused by somatotrope or lactotrope adenomas that oversecrete the respective hormones. These adenomas often retain some features of the normal regulation described earlier, thus permitting pharmacological modulation of secretion—an important modality in therapy.
Clinical Manifestations. GH excess causes distinct clinical syndromes depending on the age of the patient. If the epiphyses are unfused, GH excess causes increased longitudinal growth, resulting in gigantism. In adults, GH excess causes acromegaly. The symptoms and signs of acromegaly (e.g., arthropathy, carpal tunnel syndrome, generalized visceromegaly, macroglossia, hypertension, glucose intolerance, headache, lethargy, excess perspiration, and sleep apnea) progress slowly, and diagnosis often is delayed. Mortality is increased at least 2-fold relative to age-matched controls, predominantly due to increased death from cardiovascular disease.
Hyperprolactinemia is a relatively common endocrine abnormality that can result from hypothalamic or pituitary diseases that interfere with the delivery of inhibitory dopaminergic signals, from renal failure, from primary hypothyroidism associated with increased TRH levels, or from treatment with dopamine receptor antagonists. Most often, hyperprolactinemia is caused by prolactin-secreting pituitary adenomas—either microadenomas (≤1 cm in diameter) or macroadenomas (>1 cm in diameter). Manifestations of prolactin excess in women include galactorrhea, amenorrhea, and infertility. In men, hyperprolactinemia causes loss of libido, erectile dysfunction, and infertility.
Diagnosis of Somatotropin Hormone Excess. Although acromegaly should be suspected in patients with the appropriate symptoms and signs, diagnostic confirmation requires the demonstration of increased circulating GH or IGF-1. The "gold standard" diagnostic test for acromegaly is the oral glucose tolerance test. Whereas normal subjects suppress their GH level to <1 ng/mL in response to an oral glucose challenge (the absolute value may vary depending on the sensitivity of the assay), patients with acromegaly either fail to suppress or show a paradoxical increase in GH level.
In patients with hyperprolactinemia, the major question is whether conditions other than a prolactin-producing adenoma are responsible for the elevated prolactin level. A number of medications that inhibit DA signaling can cause moderate elevations in prolactin (e.g., antipsychotics, metoclopramide), as can primary hypothyroidism, pituitary mass lesions that interfere with dopamine delivery to the lactotropes, and pregnancy. Thus thyroid function and pregnancy tests are indicated, as is magnetic resonance imaging (MRI) to look for a pituitary adenoma or other defect that might elevate serum prolactin.
Impaired Production of the Somatotropic Hormones. Prolactin deficiency may result from conditions that damage the pituitary gland, but prolactin is not given as part of endocrine replacement therapy.
Clinical Manifestations of Growth Hormone Deficiency. Clinically, children with GH deficiency present with short stature, delayed bone age, and a low age-adjusted growth velocity. Specific etiologies associated with GH deficiency in children include genetic disorders that affect pituitary development and can cause deficiencies of multiple pituitary hormones, pituitary or hypothalamic tumors, previous CNS irradiation, and infiltrative processes such as histiocytosis. In most patients, however, the deficiency is idiopathic, with normal production of other pituitary hormones and no obvious structural abnormalities.
GH deficiency in adults does not impair linear growth, which ceases with closure of the epiphyses. Rather, GH deficiency in adults is associated with decreased muscle mass and exercise capacity, decreased bone density, impaired psychosocial function, and increased mortality from cardiovascular causes, probably secondary to deleterious changes in fat distribution, increases in circulating lipids, and increased inflammation (Molitch et al., 2006).
Diagnosis of Growth Hormone Deficiency. Because GH secretion is highly pulsatile, random sampling of serum GH is insufficient to diagnose GH deficiency. Whereas tests for substances that provide an estimate of integrated GH levels over time (e.g., IGF-1 and IGFBP-3) are more useful, provocative tests usually are required. After excluding other causes of poor growth, the diagnosis of GH deficiency should be entertained in children with height >2 to 2.5 standard deviations below normal, delayed bone age, a decreased growth velocity, and a predicted adult height substantially below the mean parental height. In this setting, a serum GH level <10 ng/mL following provocative testing (e.g., insulin-induced hypoglycemia, arginine, levodopa, clonidine, or glucagon) indicates GH deficiency; a stimulated value <5 ng/mL reflects severe deficiency.
In adults, overt GH deficiency usually results from pituitary lesions caused by a functioning or nonfunctioning pituitary adenoma, secondary to trauma, or related to surgery or radiotherapy for a pituitary or suprasellar mass (Molitch et al., 2006). Almost all patients with multiple deficits in other pituitary hormones also have deficient GH secretion, and some experts incorporate the number of other pituitary deficiencies into a diagnostic algorithm for diagnosing GH deficiency. Others accept a serum IGF-1 level below the age- and sex-adjusted normal range as indicative of GH deficiency in a patient with known pituitary disease. The converse is not true because an IGF-1 level within the normal range does not exclude adult GH deficiency. Some experts require an inadequate GH response to provocative testing (i.e., a value <5 ng/mL), with either insulin-induced hypoglycemia or a combination of Arg and GHRH as the preferred stimulus for GH secretion. Finally, in patients with known hypothalamic/pituitary disease of recent onset, Arg alone can be used as the stimulus, with the hGH cutoff set at 1.4 ng/mL. The risk of false-positive provocative tests (i.e., a subnormal GH response) is increased in obese subjects.
Pharmacotherapy of Disordersof the Somatotropin Hormones
Pharmacotherapy of Growth Hormone Excess. Treatment options in gigantism/acromegaly include transphenoidal surgery, radiation, and drugs that inhibit GH secretion or action. Pituitary surgery traditionally has been the treatment of choice. In patients with microadenomas, skilled neurosurgeons can achieve cure rates of 65-85%; however, the long-term success rate for patients with macroadenomas typically is <50%. In addition, there is increasing appreciation that acromegalic patients previously considered cured by pituitary surgery actually have persistent GH excess, with its attendant complications. Pituitary irradiation may be associated with significant long-term complications, including visual deterioration and pituitary dysfunction. Thus, increased attention has been given to the pharmacological management of acromegaly, either as primary treatment or for the treatment of persistent GH excess after transphenoidal surgery or irradiation. Another area receiving increased investigation is the potential role of medical therapy before surgery to improve outcome (Carlsen et al., 2008). The favored therapy has been with SST analogs, although the GH receptor antagonist pegvisomant increasingly is used. In patients who refuse these injected treatments, DA agonists may be used, although they are much less effective.
Somatostatin Analogs. The development of synthetic analogs of SST (Figure 38–3) revolutionized the medical treatment of acromegaly. The goal of treatment is to decrease GH levels to <2.5 ng/mL after an oral glucose-tolerance test and to bring IGF-1 levels to within the normal range for age and sex. Some have argued that a basal GH level of <1 ng/mL indicates cure, whereas a basal level of >2 ng/mL is highly suggestive of persistent disease.
Chemistry. Structure-function studies of SST and its derivatives established that the amino acid residues in positions 7-10 of the SST-14 peptide (Phe-Trp-Lys-Thr) are the major determinants of biological activity. Residues Trp8 and Lys9 appear to be essential, whereas conservative substitutions at Phe7 and Thr10 are permissible. Active SST analogs retain this core segment constrained in a cyclic structure, formed either by a disulfide bond (octreotide, lanreotide, vapreotide) or an amide linkage (seglitide, pasireotide) that stabilizes the optimal conformation (Pawlikowski and Melen-Mucha, 2004). The endogenous peptides, SST-14 and SST-28, do not show specificity for SST receptor subtypes except for SST5, which preferentially binds SST-28. Some SST analogs exhibit greater selectivity. For example, the octapeptides octreotide and lanreotide bind to the SST subtypes with the following order of selectivity: SST2 > SST5 > SST3 ≫ SST1 and SST4. The cyclohexapeptide, pasireotide (SOM230), binds with high affinity to all but the SST4 receptor. Small nonpeptide agonists that exhibit high selectivity for SST receptor subtypes have been isolated from combinatorial chemical libraries; these compounds may lead to a new class of highly selective, orally active SST mimetics (Weckbecker et al., 2003).
A chimeric compound that activates SST receptors and the D2 receptor (BIM-23A387) is now in clinical trials for therapy of mixed GH- and prolactin-secreting adenomas and for nonfunctioning pituitary adenomas (Pawlikowski and Melen-Mucha, 2004). Based on the apparent formation of heterodimers between the SST2 and D2 receptors, such chimeric compounds may have efficacy for certain tumors that do not respond to either classic SST analogs or DA agonists (Florio et al., 2008).
Currently, the two somatostatin analogs used widely are octreotide and lanreotide, synthetic derivatives that have longer half-lives and bind preferentially to SST2 and SST5 receptors. Octreotide (100 μg) administered subcutaneously three times daily is virtually 100% bioactive, peak effects are seen within 30 min, serum t1/2 is ∼90 min, and duration of action is ∼12 hour. This formulation successfully controls the biochemical parameters of acromegaly in 50-60% of patients.
The need to inject octreotide three times daily poses a significant obstacle to patient compliance. A long-acting, slow-release form (sandostatin-lar depot) in which the active species is incorporated into microspheres of a biodegradable polymer greatly reduces the injection frequency. Administered intramuscularly in a dose of 20 or 30 mg once every 4 week, typically to patients who have tolerated and responded to the shorter-acting formulation, octreotide LAR is at least as effective as the regular formulation (Murray and Melmed, 2008). Like the shorter-acting formulation, the longer-acting formulation of octreotide generally is well tolerated with a similar incidence of side effects (see following discussion). A lower dose of 10 mg per injection should be used in patients requiring hemodialysis or with hepatic cirrhosis.
In addition to its effect on GH secretion, octreotide can decrease tumor size, although tumor growth generally resumes after octreotide treatment is stopped.
Lanreotide is another long-acting octapeptide SST analog that causes prolonged suppression of GH secretion when administered in a 30-mg dose intramuscularly. Although its efficacy appears comparable to that of the long-acting formulation of octreotide, its duration of action is shorter; thus, it is administered at 10- or 14-day intervals.
A supersaturated aqueous formulation of lanreotide, lanreotide autogel (somatuline depot), has recently been approved for use in the U.S. It is supplied in prefilled syringes containing 60, 90, or 120 mg lanreotide and administered by deep subcutaneous injection. Administered once every 4 weeks, lanreotide autogel provides more uniform drug levels than the depot formulation of octreotide. Results of current clinical trials are at least comparable to those with the slow-release octreotide formulation (Murray and Melmed, 2008).
Adverse Effects. GI side effects—including diarrhea, nausea, and abdominal pain—occur in up to 50% of patients receiving octreotide. In most patients, these symptoms diminish over time and do not require cessation of therapy. Approximately 25% of patients receiving octreotide develop gallbladder sludge or even gallstones, presumably due to decreased gallbladder contraction and bile secretion. In the absence of symptoms, gallstones are not a contraindication to continued use of octreotide. Compared with SST, octreotide reduces insulin secretion to a lesser extent and only infrequently affects glycemic control. Inhibitory effects on TSH secretion may lead to hypothyroidism, and thyroid function tests should be evaluated periodically. The incidence and severity of side effects associated with lanreotide are similar to those of octreotide. Perhaps related to its more global inhibition of SST receptors, pasireotide has exhibited a relatively greater impairment in glycemic control than octreotide or lanreotide. The degree to which this may limit its clinical utility is not yet established.
Other Therapeutic Uses. Somatostatin blocks not only GH secretion but also the secretion of other hormones, growth factors, and cytokines. Thus octreotide and the slow-release formulations of SST analogs have been used to treat symptoms associated with metastatic carcinoid tumors (e.g., flushing and diarrhea) and adenomas secreting vasoactive intestinal peptide (e.g., watery diarrhea). Octreotide also is used for treatment of acute variceal bleeding and for perioperative prophylaxis in pancreatic surgery (see Chapter 46 for discussion of the uses of SST analogs in GI disease). Octreotide also has significant inhibitory effects on TSH secretion, and it is the treatment of choice for patients who have thyrotrope adenomas that oversecrete TSH who are not good candidates for surgery. Finally, modified forms of octreotide labeled with indium or technetium have been used for diagnostic imaging of neuroendocrine tumors such as pituitary adenomas and carcinoids (octreoscan); modified forms labeled with β emitters such as 90Y have been used in selective destruction of SST2 receptor-positive tumors.
Novel uses under evaluation include the treatment of eye diseases associated with excessive proliferation and inflammation (e.g., Graves' orbitopathy and diabetic retinopathy), diabetic nephropathy, and various diseases associated with inflammation (e.g., rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, and psoriasis).
Growth Hormone Antagonists. Pegvisomant (somavert) is a GH receptor antagonist that is FDA-approved for the treatment of acromegaly. Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 secretion (Figure 38–5).
Pegvisomant is administered subcutaneously as a 40-mg loading dose under physician supervision, followed by self-administration of 10 mg per day. Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervals to a maximum of 40 mg per day. Pegvisomant should not be used in patients with an unexplained elevation of hepatic transaminases, and liver function tests should be monitored in all patients. In addition, lipohypertrophy has occurred at injection sites, sometimes requiring cessation of therapy; this is believed to reflect the inhibition of direct actions of GH on adipocytes. Because of concerns that loss of negative feedback by GH and IGF-1 may increase the growth of GH-secreting adenomas, careful follow-up by pituitary MRI is strongly recommended, although this may change as more data become available (Jimenez et al., 2008). Pegvisomant differs structurally from native GH and induces the formation of specific antibodies in ∼15% of patients despite the covalent coupling of Lys residues to 4-5 molecules of a polyethylene glycol polymer per modified GH molecule. Nevertheless, the development of tachyphylaxis due to these antibodies has not been reported.
In clinical trials, pegvisomant at higher doses decreased serum IGF-1 to normal age- and sex-adjusted levels in >90% of patients and significantly improved clinical parameters such as ring size, soft-tissue swelling, excessive perspiration, and fatigue. Thus pegvisomant provides a highly effective alternative for use in patients who have not responded to SST analogs, either as sole therapy or as a temporizing measure while waiting for radiation therapy to achieve its full effect; it also is receiving increased scrutiny as first-line therapy.
Therapy of Prolactin Excess. The therapeutic options for patients with prolactinomas include transphenoidal surgery, radiation, and treatment with DA receptor agonists that suppress prolactin production via activation of D2 receptors. The surgical success rates are 75% for microadenomas and 33% for macroadenomas. Given these results, D2 receptor agonists are widely recognized as the treatment of choice for most patients (Gillam et al., 2006).
Dopamine Receptor Agonists
These agents generally decrease both prolactin secretion and the size of the adenoma, thereby improving both the endocrine abnormalities and neurological symptoms caused directly by the adenoma (including visual field deficits). Over time, especially with cabergoline, the prolactinoma may decrease in size to the extent that the drug can be discontinued without recurrence of the hyperprolactinemia. Some experts therefore recommend treatment with a dopamine receptor agonist for a minimum of 2 years, followed by a trial of dopamine agonist withdrawal in patients who have responded to dopamine agonist therapy with normalization of prolactin and disappearance of the tumor on MRI scanning (Gillam et al., 2006).
Patients with prolactinomas who wish to become pregnant comprise a special subset of hyperprolactinemic patients because drug safety during pregnancy becomes an important consideration. The dopamine agonists described here relieve the inhibitory effect of prolactin on ovulation and permit most patients with prolactinomas to become pregnant. Clinical experience also indicates that many patients can discontinue the dopaminergic agonist during pregnancy without clinically significant tumor growth. Although drug therapy ideally is discontinued before pregnancy to avoid any fetal exposure, most experts discontinue therapy after pregnancy is confirmed and carefully follow for symptoms or signs of pituitary mass effect throughout gestation. Because of its greater track record, bromocriptine generally is recommended for fertility induction in patients with hyperprolactinemia. Substantial clinical use with cabergoline has not revealed adverse maternal or fetal effects (Colao et al., 2008a), but most endocrinologists still prefer bromocriptine in this setting. Although not definitive, there are data linking quinagolide with fetal abnormalities (reviewed by Gillam et al., 2006), and it should not be used when pregnancy is intended.
Bromocriptine. Bromocriptine (parlodel) is the dopamine receptor agonist against which newer agents are compared.
Chemistry. Bromocriptine is a semisynthetic ergot alkaloid (Figure 38–6) that interacts with D2 receptors to inhibit spontaneous and TRH-induced release of prolactin; to a lesser extent, it also activates D1 receptors.
Absorption, Distribution, and Elimination. Although a large fraction of the oral dose of bromocriptine is absorbed, only 7% of the dose reaches the systemic circulation because of a high extraction rate and extensive first-pass metabolism in the liver. Bromocriptine has a relatively short elimination t1/2 (between 2 and 8 hours) and thus is usually administered in divided doses (see Adverse Effects). To avoid the need for frequent dosing, a slow release oral form is available outside of the U.S. Bromocriptine may be administered vaginally (2.5 mg once daily), reportedly with fewer gastrointestinal side effects.
Therapeutic Uses. Bromocriptine normalizes serum prolactin levels in 70-80% of patients with prolactinomas and decreases tumor size in >50% of patients, including those with macroadenomas. Typically, bromocriptine does not cure the underlying adenoma, and hyperprolactinemia and tumor growth recur upon cessation of therapy.
Adverse Effects. Frequent side effects of bromocriptine include nausea and vomiting, headache, and postural hypotension, particularly on initial use. Less frequently, nasal congestion, digital vasospasm, and CNS effects such as psychosis, hallucinations, nightmares, or insomnia are observed. These adverse effects can be diminished by starting at a low dose (1.25 mg) administered at bedtime with a snack. After 1 week, a morning dose of 1.25 mg can be added. If clinical symptoms persist or serum prolactin levels remain elevated, the dose can be increased gradually, every 3-7 days, to 5 mg two or three times a day as tolerated. Patients often develop tolerance to the adverse effects of bromocriptine. Those who do not respond to bromocriptine or who develop intractable side effects often respond better to cabergoline. At higher concentrations, bromocriptine is used in the management of acromegaly, as noted earlier, and at still higher concentrations is used in the management of Parkinson's disease (Chapter 22).
Dopamine receptor agonists used in the treatment of prolactinomas. The structures of dopamine, the predominant regulator of prolactin secretion, and of dopaminergic agonists that are used to inhibit prolactin secretion are shown. Bromocriptine and cabergoline are ergot derivatives, whereas quinagolide is not. The β-phenylethylamine region of structural similarity between dopamine and the agonists is shown in red.
The hypothalamic-pituitary-gonadal axis. A single hypothalamic releasing factor, gonadotropin-releasing hormone (GnRH), controls the synthesis and release of both gonadotropins (LH and FSH) in males and females. Gonadal steroid hormones (androgens, estrogens, and progesterone) exert feedback inhibition at the level of the pituitary and the hypothalamus. The preovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus. Inhibins, a family of polypeptide hormones produced by the gonads, specifically inhibit FSH secretion by the pituitary.
Cabergoline. Cabergoline (dostinex) is an ergot derivative with a longer t1/2 (∼65 hours), higher affinity, and greater selectivity for the D2 receptor (approximately four times more potent) than bromocriptine. It undergoes significant first-pass metabolism in the liver, and the precise oral availability is not known.
Therapeutic Uses. Cabergoline is FDA-approved for the treatment of hyperprolactinemia and has become the preferred drug in most settings for this disorder. Its greater efficacy in decreasing serum prolactin in patients with hyperprolactinemia may reflect improved adherence to therapy due to decreased side effects. Therapy is initiated at a dose of 0.25 mg twice a week or 0.5 mg once a week. If the serum prolactin remains elevated, the dose can be increased to a maximum of 1.5-2 mg two or three times a week as tolerated; the dose should not be increased more often than once every 4 weeks.
Cabergoline induces remission in a significant number of patients with prolactinomas, and a trial of drug discontinuation is advocated for the subset of patients with normalization of prolactin and disappearance of a detectable pituitary lesion on MRI scanning.
At higher doses, cabergoline is used in some patients with acromegaly and is now under investigation for patients with Cushing's disease due to corticotrope adenomas (Chapter 42).
Adverse Effects. Compared to bromocriptine, cabergoline has a much lower tendency to induce nausea, although it still may cause hypotension and dizziness. Cabergoline has been linked to valvular heart disease, an effect proposed to reflect agonist activity at the serotonin 5-HT2B receptor. A similar effect has been seen with pergolide (see later). Thus echocardiographic assessment seems appropriate for patients receiving chronic therapy with cabergoline, particularly those on higher doses (Colao et al., 2008b).
Quinagolide. Quinagolide (norprolac) is a non-ergot D2 agonist (Figure 38–6) with a t1/2 (22 hours) between those of bromocriptine and cabergoline. Quinagolide is administered once daily at doses of 0.1-0.5 mg/day. It is not approved by the FDA but has been used extensively in Europe and Canada.
Pergolide. Pergolide (permax), an ergot derivative FDA-approved for treatment of Parkinson disease, also was used off label to treat hyperprolactinemia. In part due to concerns of valvular heart disease, pergolide has been withdrawn from the market.
Therapy of Growth Hormone Deficiency
The pharmacology of somatotropic hormone deficiency is focused on GH because prolactin is not used clinically. Replacement therapy is well established in GH-deficient children and is gaining wider acceptance for GH-deficient adults. Several other indications are also approved, as described later. More recently, recombinant human IGF-1 has been approved for use in patients with mutations in the GH receptor that impair its action, as well as in GH-deficient children who develop antibodies against the recombinant hGH preparation. Although once marketed, a synthetic GHRH analog is no longer available.
Recombinant Human Growth Hormone. Humans do not respond to GH from nonprimate species. In earlier times, GH for therapeutic use was purified from human cadaver pituitaries; it thus was available in very limited quantities and in the mid-1980s was linked to the transmission of Creutzfeldt-Jakob disease. Currently, human GH is produced by recombinant DNA technology, thereby providing virtually unlimited amounts of the hormone while eliminating the risk of disease transmission associated with the pituitary-derived preparations.
Somatropin refers to the many GH preparations whose sequences match that of native GH (accretropin, genotropin, humatrope, norditropin, nutropin, omnitrope, saizen, serostim, tev-tropin, valtropin, and zorbtive); somatrem refers to a derivative of GH with an additional methionine at the amino terminus that is no longer available in the U.S.
Chemistry. Although the bacterial or yeast systems used to express the recombinant GH subtly affect the structures of these preparations, they all have similar biological actions and potencies (3 IU/mg). An FDA-approved, encapsulated form of somatropin (nutropin depot) injected intramuscularly, either monthly (1.5 mg/kg body weight) or every 2 weeks (0.75 mg/kg body weight), has been discontinued by the manufacturer.
Pharmacokinetics. As a peptide hormone, GH is administered subcutaneously, with a bioavailability of 70%. Although the circulating t1/2 of GH is only 20 minutes, its biological t1/2 is considerably longer, and once-daily administration is sufficient. To match the usual pattern of secretion, GH typically is administered at bedtime, although this is not essential.
Indications for Growth Hormone Treatment. GH deficiency in children is a well-accepted cause of short stature, and replacement therapy has been used for half a century to treat children with severe GH deficiency. With the advent of essentially unlimited supplies of recombinant GH, therapy has been extended to children with other conditions associated with short stature despite adequate GH production, including Turner's syndrome, Noonan's syndrome, Prader-Willi syndrome, chronic renal insufficiency, children born small for gestational age, and children with idiopathic short stature (i.e., >2.25 standard deviations below mean height for age and sex but with normal laboratory indices of growth hormone levels).
Attention also has shifted to the proper role of GH therapy in GH-deficient adults. The consensus of experts is that at least the most severely affected GH-deficient adults may benefit from GH replacement therapy (Molitch et al., 2006). The FDA also has approved GH therapy for AIDS-associated wasting and for malabsorption associated with the short bowel syndrome. The latter indication is based on the finding that GH stimulates the adaptation of gastrointestinal epithelial cells.
Contraindications. Based on controlled clinical trials showing increased mortality, GH should not be used in patients with acute critical illness due to complications after open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. GH also should not be used in patients who have any evidence of neoplasia, and antitumor therapy should be completed before GH therapy is initiated. Other contraindications include proliferative retinopathy or severe nonproliferative diabetic retinopathy. In Prader-Willi syndrome, sudden death has been observed when GH was given to children who were severely obese or who had severe respiratory impairment.
Therapeutic Uses. In GH-deficient children, somatropin typically is administered in a dose of 25-50 μg/kg per day subcutaneously in the evening; higher daily doses (e.g., 50-67 μg/kg) are employed for patients with Noonan's syndrome or Turner's syndrome, who have partial GH resistance. In children with overt GH deficiency, measurement of serum IGF-1 levels sometimes is used to monitor initial response and compliance; long-term response is monitored by close evaluation of height, sometimes in conjunction with measurements of serum IGF-1 levels (Cohen et al., 2007). Although the most pronounced increase in growth velocity occurs during the first 2 years of therapy, GH is continued until the epiphyses are fused and also may be extended into the transition period from childhood to adulthood.
In view of the effects of GH on bone density and visceral adiposity and the manifestations of GH deficiency in adults, many experts now continue therapy into adulthood for children with GH deficiency (Radovick and DiVall, 2007). However, many patients who were GH deficient in childhood based on provocative testing, especially those with idiopathic, isolated GH deficiency, respond normally to provocative tests as adults. Thus, it is essential to confirm GH deficiency after full growth has been achieved, ideally after discontinuation of GH replacement for at least 1 month, to identify patients who will benefit from continuing GH treatment.
For adults, weight-based dosing largely has been supplanted by initiation with relatively low doses irrespective of weight, followed by dose titration as tolerated to raise IGF-1 levels to the mid-normal range adjusted for age and sex. A typical starting dose is 150-300 μg per day, with higher doses used in younger patients transitioning from pediatric therapy; lower doses are used in older patients (e.g., >60 years of age). Either an elevated serum IGF-1 level or persistent side effects mandates a decrease in dose; conversely, the dose can be increased (typically by 100-200 μg per day) if serum IGF-1 has not reached the normal range after 2 months of GH therapy. Because estrogen inhibits GH action, women taking oral—but not transdermal—estrogen may require larger GH doses to achieve the target IGF-1 level. In the setting of AIDS-related wasting, considerably higher doses (e.g., 100 μg/kg) have been used. Studies are also underway to assess the effect of GH therapy on reducing visceral adiposity and increasing lean body mass in HIV-infected patients with the adipose redistribution syndrome (Grunfeld et al., 2007; Lo et al., 2008).
Based on the known age-related decline in GH levels, the use of GH therapy to ameliorate or even reverse the consequences of aging has been widely promoted. Many of the studies supporting this use were not placebo controlled and involved small numbers of subjects. Moreover, one review concluded that there was no significant improvement in strength or aerobic performance with GH therapy in elderly subjects (Liu et al., 2007). Thus, this remains an area of considerable debate. In violation of regulations and standard medical practice, some athletes also use injected GH preparations as anabolic agents to enhance performance (Gibney et al., 2007). In addition to the parenteral GH preparations, oral preparations containing "stacked" amino acids that reputedly stimulate GH release have been marketed as nutritional supplements. Despite the absence of validation in controlled trials, these formulations are part of multibillion dollar anti-aging and performance-enhancing programs (Olshansky and Perls, 2008).
Adverse Effects of Growth Hormone Therapy. In children, GH therapy is associated with remarkably few side effects. Rarely, generally within the first 8 weeks of therapy, patients develop intracranial hypertension, with papilledema, visual changes, headache, nausea, and/or vomiting. Because of this, funduscopic examination is recommended at the initiation of therapy and at periodic intervals thereafter. Leukemia has been reported in some children receiving GH therapy; a causal relationship has not been established, and conditions associated with GH deficiency (e.g., Down's syndrome, cranial irradiation for CNS tumors) probably explain the apparent increased incidence of leukemia. Despite this, the consensus is that GH should not be administered in the first year after treatment of pediatric tumors, including leukemia, or during the first 2 years after therapy for medulloblastomas or ependymomas. Because an increased incidence of type 2 diabetes mellitus has been reported, fasting glucose levels should be followed periodically during therapy. Finally, too-rapid growth may be associated with slipped epiphyses or scoliosis, although a causal link with GH has not been proven.
Side effects associated with the initiation of GH therapy in adults include peripheral edema, carpal tunnel syndrome, arthralgias, and myalgias, which occur most frequently in patients who are older or obese and generally respond to a decrease in dose. These volume-related adverse effects occur less frequently with standard-dose rather than weight-based regimens. Although there are potential concerns about impaired glucose tolerance secondary to anti-insulin actions of GH, this generally has not been a major problem at the recommended doses. In fact, changes in visceral fat composition associated with GH replacement may improve insulin sensitivity in some patients.
Drug Interactions. The effects of estrogen on GH therapy were noted earlier. This effect is much less marked with transdermal estrogen preparations. Recent studies suggest that GH therapy can increase the metabolic inactivation of glucocorticoids in the liver. Thus, GH may precipitate adrenal insufficiency in patients with occult secondary adrenal insufficiency or in patients receiving replacement doses of glucocorticoids. This has been attributed to the inhibition of the type 1 isozyme of steroid 11β-hydroxysteroid dehydrogenase, which normally converts inactive cortisone into the active 11-hydroxy derivative cortisol (Chapter 42).
Insulin-like Growth Factor 1 (IGF-1)
Based on the hypothesis that GH predominantly acts via increases in IGF-1, there has been a longstanding interest in developing IGF-1 preparations for therapeutic use. To this end, recombinant human IGF-1 (mecasermin, increlex) and a combination of recombinant human IGF-1 with its binding protein, IGFBP-3 (mecasermin rinfabate; iplex), are FDA-approved. The latter formulation was subsequently discontinued for use in short stature due to patent issues, although it remains available for other conditions such as severe insulin resistance, muscular dystrophy, and HIV-related adipose redistribution syndrome.
Absorption, Distribution, and Elimination. Mecasermin is administered by subcutaneous injection and absorption is virtually complete. As discussed earlier, IGF-1 in circulation is bound by six proteins; a ternary complex that includes IGFBP-3 and the acid labile subunit accounts for >80% of the circulating IGF-1. This protein binding prolongs the t1/2 of IGF-1 to ∼6 hours. Both the liver and kidney have been shown to metabolize IGF-1.
Therapeutic Uses. Mecasermin is FDA-approved for patients with impaired growth secondary to mutations in the GH receptor or postreceptor signaling pathway, patients with GH deficiency who develop antibodies against GH that interfere with its action, and the very rare patients with IGF-1 gene defects that lead to primary IGF-1 deficiency (Collet-Solberg and Misra, 2008). Typically the starting dose is 40-80 μg/kg per dose twice daily by subcutaneous injection, with a maximum of 120 μg/kg per dose twice daily.
Clinical trials also have examined the efficacy of mecasermin in the much larger cohort of patents with impaired growth secondary to GH deficiency or with idiopathic short stature. In these settings, mecasermin stimulates linear growth but is less effective than conventional therapy using recombinant GH, suggesting direct effects of GH on linear growth independent of IGF-1. Although further study is needed, mecasermin should be reserved for therapy in patients with FDA-approved indications and is unlikely to replace GH as preferred therapy for most patients with GH deficiency or short stature.
Adverse Effects. Side effects of mecasermin include hypoglycemia and lipohypertrophy, both presumably secondary to activation of the insulin receptor. To diminish the frequency of hypoglycemia, mecasermin should be administered shortly before or after a meal or snack. Lymphoid tissue hypertrophy, including enlarged tonsils, also is seen and may require surgical intervention. Other adverse effects are similar to those associated with GH therapy and include intracranial hypertension, slipped epiphyses, and scoliosis.
Contraindications. Mecasermin should not be used for growth promotion in patients with closed epiphyses. It should not be given to patients with active or suspected neoplasia and should be stopped if evidence of neoplasia develops.
Sermorelin. Sermorelin (geref) is a synthetic form of human GHRH that corresponds in sequence to the first 29 amino acids of human GHRH (a 44–amino acid peptide) and has full biological activity. Although sermorelin is FDA-approved for treatment of GH deficiency and as a diagnostic agent to differentiate between hypothalamic and pituitary disease, the drug was withdrawn from the U.S. market in late 2008.