Section XII - Hormones and Hormone Antagonists pps

Section XII. Hormones and Hormone Antagonists Chapter 56. Pituitary Hormones and Their Hypothalamic Releasing Factors Overview This chapter covers the diagnostic and therapeutic uses of some of the pituitary hormones— including growth hormone (GH), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and oxytocin—as well as the therapeutic approaches to conditions of excess secretion of GH and prolactin. Also discussed are the clinical and diagnostic uses of hypothalamic factors that regulate the secretion of pituitary hormones, including growth hormone-releasing hormone (GHRH), somatostatin, and gonadotropin-releasing hormone (GnRH). FSH, LH, and GnRH also are discussed in Chapters 58: Estrogens and Progestins and 59: Androgens. Considered elsewhere are corticotropin and corticotropin-releasing hormone (Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones) and thyrotropin and thyrotropin releasing hormone (Chapter 57: Thyroid and Antithyroid Drugs). Pituitary Hormones and Their Hypothalamic Releasing Factors: Introduction The peptide hormones of the anterior pituitary are essential for the regulation of growth and development, reproduction, responses to stress, and intermediary metabolism. Their synthesis and secretion are controlled by hypothalamic hormones and by hormones from the peripheral endocrine organs. A large number of disease states as well as a diverse group of drugs also affect their secretion. The complex interactions among the hypothalamus, pituitary, and peripheral endocrine glands provide elegant examples of integrated feedback regulation. Clinically, an improved understanding of the mechanisms that underlie these interactions provides the rationale for diagnosing and treating endocrine disorders and for predicting certain side effects of drugs that affect the endocrine system. Moreover, the elucidation of the structures of the anterior pituitary hormones and hypothalamic releasing hormones together with advances in protein chemistry have made it possible to produce synthetic peptide agonists and antagonists that have important diagnostic and therapeutic applications. Ten anterior pituitary hormones have been identified in vertebrates; these can be classified into three different groups based on their structural features (Table 56–1). Growth hormone (GH) and prolactin belong to the somatotropic family of hormones, which in human beings also includes placental lactogen. The glycoprotein hormones—thyrotropin (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)—share a common -subunit but have different -subunits that determine their distinct biological activities. In human beings, the glycoprotein hormone family also includes placental chorionic gonadotropin (CG). Corticotropin (adrenocorticotrophic hormone; ACTH), the two melanocyte-stimulating hormones ( - and -MSH), and the two lipotropins represent a family of hormones derived from proopiomelanocortin by proteolytic processing. Except for -MSH and the lipotropins, these pituitary hormones all play significant roles in human health and disease. The synthesis and release of anterior pituitary hormones are influenced by the central nervous system. Their secretion is positively regulated by a group of polypeptides referred to as hypothalamic releasing hormones. These hormones are released from hypothalamic neurons in the region of the median eminence, and they reach the anterior pituitary through the hypothalamic- adenohypophyseal portal system. The hypothalamic releasing hormones include growth hormone– releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH). Somatostatin, another hypothalamic peptide, negatively regulates the pituitary secretion of growth hormone and thyrotropin. Finally, the catecholamine dopamine inhibits the secretion of prolactin by lactotropes. As discussed further in Chapter 30: Vasopressin and Other Agents Affecting the Renal Conservation of Water, the posterior pituitary gland, also known as the neurohypophysis, contains nerve axons arising from distinct populations of neurons in the supraoptic and paraventicular nuclei that synthesize either arginine vasopressin or oxytocin. Oxytocin plays important roles in labor and parturition and in milk let-down, as discussed below. Growth Hormone The gene encoding human growth hormone (GH) resides on the long arm of chromosome 17, which also contains four related genes: three different variants of placental lactogen and a GH variant expressed in the syncytiotrophoblast (chorionic somatotropin). Secreted GH is a heterogeneous mixture of peptides that can be distinguished on the basis of size or charge; the principal 22,000- dalton form is a single polypeptide chain of 191 amino acids 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 ( 20,000 daltons) with equal bioactivity that makes up 5% to 10% of circulating GH. Additional GH species are found in serum, but their physiological significance is unclear. Approximately 45% of the 22,000-dalton and 25% of the 20,000-dalton GH in circulation are bound by a binding protein that contains the extracellular domain of the GH receptor (see below). This GH-binding protein may serve as a reservoir of growth hormone, as the biological half-life of GH complexed to it is approximately 10 times that of unbound GH. Alternatively, the binding protein may decrease GH bioactivity by preventing it from binding to its receptor in target tissues. Regulation of Growth Hormone Secretion Growth hormone, the most abundant anterior pituitary hormone, is synthesized and secreted by somatotropes. These cells account for about 50% of hormone-secreting cells of the anterior pituitary and cluster at its lateral wings. Daily GH secretion varies throughout life; secretion is high in children, reaches maximal levels during adolescence, and then decreases in an age-related manner in adulthood. GH secretion occurs in discrete but irregular pulses. Between these pulses, circulating GH falls to levels that are undetectable with current assays. The amplitude of secretory pulses is maximal at night, and the most consistent period of GH secretion is shortly after the onset of deep sleep. Because of this episodic release, random measurements of GH are of little value in the diagnosis of growth hormone deficiency, and provocative tests are required (see below). The regulation of GH secretion is illustrated in Figure 56–1. GHRH, produced by hypothalamic neurons found predominantly in the arcuate nucleus, stimulates growth hormone secretion by binding to a specific G protein–coupled receptor on somatotropes, elevating both intracellular cyclic AMP and Ca 2+ concentrations. Somatostatin, which is synthesized by more widely distributed neurons as well as by neuroendocrine cells in the gastrointestinal tract and pancreas, inhibits growth hormone secretion. Somatostatin is synthesized from a 92–amino acid precursor and processed by proteolytic cleavage to generate two predominant forms—somatostatin-14 and somatostatin-28. The somatostatins exert their effects by binding to and activating a family of G protein–coupled receptors. The consequences of receptor activation include inhibition of cyclic AMP accumulation, activation of K + channels, and activation of tyrosine phosphatase. Five somatostatin receptor subtypes have been identified, each of which binds somatostatin with nanomolar affinity; whereas receptor types 1 to 4 (abbreviated sst 1-4 or SSTR1-4) bind the two somatostatins with approximately equal affinity, type 5 (sst 5 , SSTR5) has a 10- to 15-fold greater selectivity for somatostatin-28 (Patel, 1999). It appears that the SSTR2 and SSTR5 receptors are most important for regulation of GH secretion. There is evidence supporting both direct effects of somatostatin on somatotropes and indirect effects mediated via GHRH neurons in the arcuate nucleus. As discussed below, somatostatin analogs play an important role in the therapy of syndromes of GH excess such as acromegaly. Figure 56–1. 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 and mediated by IGF-1. See text for discussion of the other agents that modulate GH secretion. Appreciation of a third component of regulation of GH secretion arose from studies of GH secretogogues (Smith et al. , 1999). The finding that peptide derivatives of Leu- and Met- enkephalins stimulate growth hormone release has led to the development of additional peptide and nonpeptide GH secretogogues that stimulate GH secretion via a G protein–coupled receptor distinct from the GHRH receptor (Howard et al. , 1996). This GH-secretogogue receptor is expressed on somatotropes as well as on GHRH neurons in the arcuate nucleus, suggesting that GH secretogogues stimulate GH release both by direct actions on the pituitary and by indirect effects on GHRH neurons. Intriguingly, both GH and somatostatin inhibit the activation of these neurons. This inhibition by GH indicates a direct feedback action of GH, while the inhibition by somatostatin suggests that an important component of the inhibition of GH secretion by somatostatin is exerted in the hypothalamus rather than in the pituitary. The clinical utility of GH secretogogues in patients with growth hormone deficiency is an area of active investigation, as is the putative endogenous ligand that activates the GH-secretogogue receptor. Although their specific sites of action are not fully understood, several neurotransmitters, drugs, metabolites, and other stimuli also affect GH secretion by modulating the release of GHRH and/or somatostatin. Dopamine, 5-hydroxytryptamine, and 2 -adrenergic receptor agonists stimulate GH release, whereas -adrenergic receptor agonists, free fatty acids, and insulin-like growth factor-1 (IGF-1, see below) and GH itself inhibit release. Hypoglycemia stimulates growth hormone release, as do exercise, stress, emotional excitement, and ingestion of protein-rich meals. In contrast, administration of glucose in an oral glucose-tolerance test suppresses GH secretion in normal subjects. These observations form the basis for provocative tests to assess the ability of the pituitary to secrete GH. Provocative stimuli include arginine, glucagon, insulin-induced hypoglycemia, clonidine, and the dopamine precursor levodopa; these agents all increase circulating GH levels in normal subjects within 45 to 90 minutes. At present, insulin-induced hypoglycemia is the test advocated by the Growth Hormone Research Society (Anonymous, 1998), whereas the United States Food and Drug Administration (FDA) requires two independent tests of GH deficiency to establish the diagnosis. When excess GH secretion is suspected (see below), the failure of an oral glucose load to suppress GH is diagnostically useful. Finally, as described below, GH secretion in response to GHRH can be used to distinguish pituitary disease from hypothalamic disease. Molecular and Cellular Bases of Growth Hormone Action All of the effects of GH result from its interactions with the GH receptor, as evidenced by the severe phenotype of rare patients with homozygous mutations of the GH-receptor gene (the Laron syndrome of GH-resistant dwarfism). The GH receptor is a widely distributed cell-surface receptor that belongs to the cytokine receptor superfamily and shares structural similarity with the prolactin receptor, the erythropoietin receptor, and several of the interleukin receptors (Finidori et al. , 2000). Like other members of the cytokine receptor family, the GH receptor contains an extracellular domain that binds GH, a single membrane-spanning region, and an intracellular domain that mediates signal transduction. Receptor activation results from the binding of a single GH molecule to two identical receptor molecules (de Vos et al. , 1992). The net result is the formation of a ligand- occupied receptor dimer that presumably brings the intracellular domains of the receptor into close proximity, thereby activating cytosolic components critical for cell signaling. As determined from cDNA cloning and sequencing (Leung et al. , 1987), the mature human GH receptor contains 620 amino acids, 260 of which are extracellular and 350 of which are cytoplasmic. The formation of the GH-GH receptor ternary complex is initiated by a high-affinity interaction of GH with a receptor monomer, exposing a second site of lower affinity on GH that recruits a second receptor molecule to the complex. Interestingly, GH analogs have been engineered with a disrupted second receptor-binding site; these analogs cannot induce receptor dimerization. One such analog, pegvisomant, behaves as a GH antagonist and has shown promise in the treatment of acromegaly (Trainer et al. , 2000; see below). In addition to the full-length GH receptor, truncated forms of the receptor also have been described. A circulating form of the receptor, called GH-binding protein, is formed by proteolytic cleavage of the extracellular domain of the receptor from its transmembrane segment. GH-binding protein has been reported to delay the clearance of circulating GH and increase its activity in vitro, but its biological role remains unknown. Truncated, membrane-anchored forms of the receptor also have been described. Again, the physiological roles of these proteins, which apparently result from alternative splicing events and constitute a small fraction of the receptor population, are unknown, although they inhibit GH action in cultured cell models. Truncated forms of the GH receptor also have been found in one kindred with growth-hormone insensitivity and short stature (Ayling et al. , 1997). These patients are heterozygous for the receptor mutation, suggesting that the truncated receptors behave as dominant negative inhibitors of GH signaling. The ligand-occupied receptor dimer does not have inherent tyrosine kinase activity, but it does provide 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. These include Stat proteins (signal transducers and activators of transcription), Shc (an adapter protein that regulates the Ras/MAP kinase signaling pathway), and IRS-1 and IRS- 2 (insulin-receptor substrate proteins that activate the phosphatidyl inositol-3 kinase regulatory pathway) (see Figure 56–2). Figure 56–2. Mechanism of Growth Hormone Action. The binding of GH to two molecules of the growth hormone receptor (GHR) induces dimerization of JAK2 and its autophosphorylation. JAK2 then phosphorylates cytoplasmic proteins that activate downstream signaling pathways (PI3 kinase, ras, raf, MAPK) that ultimately affect gene expression. The arrows indicate the presumed order of activation in the signaling pathway; the figure does not reflect the localization of the intracellular molecules, which presumably exist in multicomponent signaling complexes. JAK2, janus kinase 2; IRS1, insulin receptor substrate 1; PI3 kinase, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator of transcription; SOS, product of the son of sevenless gene; MAPK, mitogen- activated protein kinase; MEK, MAPK kinase; SHC and Grb2, adapter proteins. Although GH acts directly on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesis, its anabolic and growth-promoting effects are mediated indirectly through the induction of insulin-like growth factors (IGFs). There are two members of the IGF family: IGF-1 and IGF-2. IGF-1 is more dependent on GH and is a more potent growth factor postnatally; thus, IGF-1 appears to be the principal mediator of GH action. Most circulating IGF-1 is made in the liver, although IGF-1 produced locally in many tissues also may exert paracrine or autocrine effects on cell growth. Circulating IGF-1 is associated with a family of binding proteins that serve as transport proteins and also may mediate certain aspects of IGF-1 signaling. The essential role of IGF-1 in GH signaling is evidenced by a patient with loss-of-function mutations in both alleles of the IGF1 gene whose severe intrauterine and postnatal growth retardation was unresponsive to GH but responsive to recombinant human IGF-1 (Camacho-Hubner, et al. , 1999). Following 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, consisting of a heterotetramer with intrinsic tyrosine kinase activity. This receptor is present in essentially all tissues and binds IGF-1 and IGF-2 with high affinity; insulin also can activate the type 1 IGF receptor, but with an affinity approximately 100 times less than that of the IGFs. The type 2 IGF receptor encodes a protein that is located predominantly on intracellular membranes and is identical to the mannose-6-phosphate receptor that participates in intracellular targeting of acid hydrolases and other mannose-containing glycoproteins to lysosomes. This receptor apparently is activated specifically by IGF-2. The signal transduction pathway for the insulin receptor is described in detail in Chapter 61: Insulin, Oral Hypoglycemic Agents, and the Pharmacology of the Endocrine Pancreas. Syndromes of Growth Hormone Deficiency GH deficiency in children is a well-accepted cause of short stature, and replacement therapy has been used for more than 30 years to treat children with severe GH deficiency. More recently, GH deficiency in adults has been associated with a defined endocrinopathy that includes increased mortality from cardiovascular causes, probably secondary to deleterious changes in fat distribution and increases in circulating lipids; decreased muscle mass and exercise capacity; and impaired psychosocial function. With the ready availability of recombinant human GH, attention has shifted to the proper role of GH therapy in GH-deficient adults. While this is an area of current debate, the emerging consensus is that at least the most severely affected GH-deficient adults will benefit from GH replacement therapy. GH therapy also is approved by the FDA for AIDS-associated wasting, and its use has resulted in some benefit in patients with this condition. Based on controlled clinical trials showing increased mortality, GH should not be used in patients with acute critical illness due to complications following 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 prior to initiation of GH therapy. Diagnosis of Growth Hormone Deficiency Clinically, children with GH deficiency present with short stature and a low age-adjusted growth velocity. Most commonly, these children have an isolated deficiency of GH without other documented pathology (i.e., idiopathic, isolated GH deficiency) and are presumed to have a hypothalamic defect. Random sampling of serum GH is insufficient to diagnose GH deficiency; provocative tests are required. After excluding other causes of poor growth, the diagnosis of GH deficiency should be entertained in patients with height 2 to 2.5 standard deviations below normal, delayed bone age, a growth velocity below the 25th percentile, and a predicted adult height substantially below the mean parental height (Vance and Mauras, 1999). In this setting, a serum GH level of less than 10 g/liter following provocative testing (e.g., insulin-induced hypoglycemia, arginine, levodopa, or glucagon) indicates GH deficiency, with a stimulated value of less than 5 g/liter reflecting severe deficiency. More than 90% of adult patients with GH deficiency have overt pituitary disease due to a functioning or nonfunctioning pituitary adenoma or resulting from surgery or radiotherapy for a pituitary mass. Almost all patients with multiple deficits in other pituitary hormones also will have deficient GH secretion. According to criteria established by the FDA, a normal response to provocative stimuli is an increase in GH to serum levels 5 g/liter by radioimmunoassay or 2.5 g/liter by immunoradiometric or immunochemiluminescent assay. In contrast, the Growth Hormone Research Society has recommended diagnosis based on a stimulated GH serum level of less than 3 g/liter during insulin-induced hypoglycemia (Anonymous, 1998). Treatment of Growth Hormone Deficiency The action of GH is highly species-specific; human beings do not respond to GH from nonprimate species. Therefore, GH for therapeutic use formerly was purified from human cadaver pituitaries in very limited quantities. The production of human GH by recombinant DNA technology not only increased availability of the hormone but also alleviated concerns about Creutzfeldt-Jakob disease associated with use of the hormone purified from cadaver pituitaries. A number of recombinant preparations of human GH are approved for use in many countries. By convention, somatropin refers to GH preparations whose sequence matches that of native GH (SEROSTIM, GENOTROPIN, HUMATROPE, NUTROPIN, SAIZEN), while somatrem refers to a derivative of GH with an additional methionine at the amino terminus (PROTROPIN). Although there are subtle differences in the sources and structures of these preparations, all have similar biological actions and potencies. They typically are administered subcutaneously in the evening; although the circulating half-life of GH is only 20 minutes, its biological half-life is in the range of 9 to 17 hours, and once-daily administration is sufficient. Newer formulations are supplied in prefilled syringes, which may be more convenient for the patient, as the GH does not need refrigeration and the diluent causes less irritation at the injection site. An encapsulated form of somatropin that is injected intramuscularly once or twice per month (NUTROPIN DEPOT) has been approved by the FDA. The relative advantages of any specific formulations over others in clinical use have not been definitively established. In addition to GH, sermorelin acetate (GEREF), a synthetic form of human GHRH, has received FDA approval for treatment of idiopathic GH deficiency. Sermorelin is a peptide of 29 amino acids that corresponds in sequence to the first 29 amino acids of human GHRH (a 44–amino acid peptide) and has full biological activity. Sermorelin generally is well tolerated and is less expensive than somatropin, but at recommended doses it has been less effective than GH in clinical trials. Moreover, this agent will not work in patients whose GH deficiency results from defects in the anterior pituitary (Anonymous, 1999). Therefore, a GH response (>2 g/liter) to a test dose of sermorelin should be documented prior to initiating therapy (30 g/kg per day, given subcutaneously), and the patients must be monitored frequently to ascertain continued growth on therapy. Sermorelin also has been employed diagnostically to distinguish between pituitary and hypothalamic disease; its clinical utility in this setting is not fully established. GH is widely used for replacement therapy in GH-deficient children, whether the deficiency is congenital or acquired. It also is FDA-approved for use in children with chronic renal insufficiency (although not proven to increase adult height) and for patients with Turner's syndrome (improving adult height significantly). Recommended doses vary with indication and product, but typically a dose of 20 to 40 g/kg is administered subcutaneously either daily or 6 times per week; higher daily doses (e.g., 50 g/kg) are employed for patients with Turner's syndrome, who have partial GH resistance. Initial response and compliance can be monitored with serum IGF-1 levels, while long- term response is monitored by close evaluation of height. Although the most pronounced increase in growth velocity occurs within the first two years of therapy, GH is continued until growth ceases. In view of the increased appreciation of the effects of GH on bone density and the effects of GH deficiency in adults, it seems reasonable to continue therapy into adulthood. However, many patients who clearly were GH deficient in childhood—especially those with idiopathic, isolated GH deficiency—respond normally to provocative tests at the cessation of therapy. Thus, it is essential to confirm GH deficiency after optimal growth has been achieved so as to identify patients who will benefit from continuing GH treatment. In adults, previously recommended doses of GH now are viewed as excessive, leading to both an elevated IGF-1 concentration and a greater risk of side effects. The FDA recommends a starting dose of 3 to 4 g/kg, given once daily by subcutaneous injection, with a maximum dose of 25 g/kg in patients 35 years old and 12.5 g/kg in older patients. The Growth Hormone Research Society recommends a starting dose of 150 to 300 g/day regardless of body weight (Anonymous, 1998). Clinical response is monitored by serum IGF-1, which should be restored to the midnormal range adjusted for age and sex. Either an elevated serum IGF-1 or persistent side effects are grounds for decreasing the dose; conversely, the dose can be increased if serum IGF-1 has not reached the normal range after two months of GH therapy. In the setting of AIDS-related wasting, considerably higher doses (e.g., 100 g/kg) have been used in clinical trials. As noted above, a subset of children with growth impairment has elevated GH levels and GH resistance, most frequently secondary to mutations in the GH receptor. These patients can be treated effectively with recombinant human IGF-1 (IGEF), which is administered subcutaneously either once or twice daily in doses ranging from 40 to 120 g/kg (Ranke et al. , 1999). Although this therapy clearly is beneficial in promoting growth, the optimal regimen remains to be established. Side Effects of GH 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 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 two years after therapy for medulloblastomas or ependymomas (Blethen et al. , 1996). An increased incidence of type 2 diabetes mellitus has been reported, presumably secondary to the anti-insulin metabolic effects of GH (Cutfield et al. , 2000). In adults, side effects associated with the initiation of GH therapy include peripheral edema, carpal tunnel syndrome, arthralgia, and myalgia. These symptoms, which occur most frequently in patients who are older or more obese, generally respond to a decrease in dose. Although there are potential concerns about impaired glucose tolerance secondary to anti-insulin actions of GH, this has not been a major problem with clinical use at the recommended doses. Agents Used in Syndromes of Growth Hormone Excess 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, hypertension, glucose intolerance, headache, lethargy, excess perspiration, and sleep apnea) progress slowly, and diagnosis often is delayed. Life expectancy is shortened in these patients; mortality is increased at least two-fold relative to age-matched controls due to increased death from cardiovascular disease, upper airway obstruction, and gastrointestinal malignancies. While the diagnosis of acromegaly should be suspected in patients with the appropriate symptoms and signs, confirmation requires the demonstration of increased circulating GH or IGF-1. Generally, the first screening test is to measure serum IGF-1. Using a good assay with results compared to normal values for age and sex, a normal IGF-1 level argues strongly against the diagnosis of acromegaly. If the IGF-1 is frankly elevated or borderline or if the clinical suspicion is relatively strong, many clinicians also will measure plasma GH following administration of an oral glucose load. Using the standard radioimmunoassay for human GH, the GH level 2 hours after glucose administration normally is less than 2 g/liter in normal subjects; a higher value confirms the diagnosis of acromegaly. Treatment options in acromegaly include transphenoidal surgery, radiation, and drugs that inhibit GH secretion or action. Pituitary surgery traditionally has been viewed as the treatment of choice. In patients with microadenomas (i.e., tumors <1 cm), skilled neurosurgeons can achieve cure rates of up to 80% to 90%; however, the long-term success rate for patients with macroadenomas is considerably lower, often falling below 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. Thus, more attention has been given to the role of pharmacological management of acromegaly, either as a primary treatment modality or for the treatment of persistent GH excess following transphenoidal surgery (Newman, 1999). Somatostatin Analogs The development of analogs of somatostatin (Table 56–2) has revolutionized the medical treatment of GH excess. The most widely used analog is octreotide (SANDOSTATIN), an eight–amino acid synthetic derivative of somatostatin that has a longer half-life and binds preferentially to SSTR-2 and SSTR-5 receptors on GH-secreting tumors. Typically, octreotide (100 g) is administered subcutaneously three times daily; serum GH and IGF-1 levels are monitored to assess effectiveness of treatment. The goal is to decrease GH levels to less than 2 g/liter following an oral glucose- tolerance test and to bring IGF-1 levels to within the normal range for age and sex. Depending on the biochemical response, higher or lower octreotide doses may be used in individual patients. In addition to its effect on GH secretion, octreotide can decrease tumor size in a minority of patients. In these cases, tumor growth generally resumes after octreotide treatment is stopped. Octreotide also has significant inhibitory effects on thryotropin secretion, and it is the treatment of choice for patients who have thryotrope adenomas that oversecrete TSH and who are not good candidates for surgery. The use of octreotide in gastrointestinal disorders is discussed in Chapter 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease. Gastrointestinal 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 gallstones, presumably due to decreased gallbladder contraction and gastrointestinal transit time. In the absence of symptoms, gallstones are not a contraindication to continued use of octreotide. Compared to somatostatin, octreotide has much less of an effect on insulin secretion and in clinical studies only infrequently affects glycemic control. The need to inject octreotide three times daily poses a significant obstacle to patient compliance. A long-acting, slow-release form of octreotide (SANDOSTATIN-LAR) is a more convenient alternative that can be administered intramuscularly once every 4 weeks; the recommended dose is 20 or 30 mg. The long-acting preparation is at least as effective as the regular formulation and is used in patients who have responded favorably to a trial of the shorter-acting formulation of octreotide. Like the shorter-acting formulation, the longer-acting formulation of octreotide generally is well tolerated and has a similar incidence of side effects (predominantly gastrointestinal and/or discomfort at injection site) that do not require cessation of therapy. Lanreotide (SOMATULINE LA) is a long-acting octapeptide analog of somatostatin 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 must be administered either at 10- or 14-day intervals. One direct comparison with a limited number of patients suggested that the long-acting formulation of octreotide at recommended doses may be somewhat more effective in lowering GH levels than is lanreotide (Turner et al. , 1999). The incidence and severity of side effects associated with lanreotide are similar to those of the other somatostatin analogs. Lanreotide has not been approved by the FDA for use in the United States. [...]... Gonadotropin-Releasing Hormone and Gonadotropic Hormones The pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the related placental hormone chorionic gonadotropin (CG), are referred to as the gonadotropic hormones because of their actions on the gonads These three hormones and TSH consitute the glycoprotein family of pituitary hormones Each hormone is a... stimulated by GnRH and is further regulated by feedback effects of the gonadal hormones (Figure 56–4; see also Figure 58–2) Figure 56–4 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)... Drug Action and the Relationship Between Drug Concentration and Effect) In addition, as with steroid hormones, it has become clear that thyroid hormones have diverse nongenomic actions (Davis and Davis, 1997) Disorders of the thyroid are common They consist of two general presentations: changes in the size or shape of the gland or changes in secretion of hormones from the gland Thyroid nodules and goiter... pituitary hormone, thyrotropin, in a classic negative-feedback system The predominant actions of thyroid hormone are mediated via binding to nuclear thyroid hormone receptors and modulating transcription of specific genes In this regard, thyroid hormones share a common mechanism of action with steroid hormones, vitamin D, and retinoids, whose receptors make up a superfamily of nuclear receptors (Chin and. .. genes, and the gene encoding the -subunit maps to chromosome 6q2 1-2 3 Regulation of Gonadotropin Secretion The regulation of gonadotropin secretion is described in detail in Chapters 58: Estrogens and Progestins and 59: Androgens LH and FSH are synthesized and secreted by gonadotropes, which make up approximately 20% of the hormone- secreting cells in the anterior pituitary CG—produced only in primates and. .. be either cured or have their diseases controlled (seeBraverman and Utiger, 2000; Braverman and Refetoff, 1997) Thyroid The thyroid gland is the source of two fundamentally different types of hormones The iodothyronine hormones include thyroxine (T4) and 3,5,3'-triiodothyronine (T3); they are essential for normal growth and development and play an important role in energy metabolism The other known... iodothyronine 5'-deiodinase; Cody, 2000) These compounds are also potent competitors of thyroxine binding to transthyretin Computer graphic modeling suggests that the best structural homology between thyroid hormones and flavonoids involves their respective phenolic rings Synthesis of Thyroid Hormones The synthesis of the thyroid hormones is unique, complex, and seemingly grossly inefficient The thyroid hormones. .. Chapter 57 Thyroid and Antithyroid Drugs Overview This chapter discusses the function of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), in growth and metabolism and the regulation of thyroid function by thyroid-stimulating hormone (TSH) secreted from the pituitary Calcitonin, also secreted by the thyroid gland, is discussed in Chapter 62: Agents Affecting Calcification and Bone Turnover:... pituitary and the hypothalamus The preovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus Inhibin, a polypeptide hormone produced by the gonads, specifically inhibits FSH production by the pituitary Regulation of Release of Gonadotropin-Releasing Hormone Gonadotropin-releasing hormone (GnRH) regulates the synthesis and secretion of FSH and LH... Magnus-Levy discovered the effect of the thyroid on metabolic rate in 1895; he found that Gull's disease was characterized by a low rate of metabolism and that the administration of thyroid to hypothyroid or normal individuals increased oxygen consumption Chemistry of Thyroid Hormones The principal hormones of the thyroid gland are the iodine-containing amino acid derivatives of thyronine—(T4 and T3; . quinagolide. Gonadotropin-Releasing Hormone and Gonadotropic Hormones The pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the related placental hormone chorionic. hypothalamic releasing hormones include growth hormone releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH) Section XII. Hormones and Hormone Antagonists Chapter 56. Pituitary Hormones and Their Hypothalamic Releasing Factors Overview This chapter covers the diagnostic and therapeutic