Section XII - Hormones and Hormone Antagonists

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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.

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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 Ca2+ 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 sst1-4 or SSTR1-4) bind the two somatostatins with approximately equal affinity, type 5 (sst5, 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
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.
Somatostatin blocks not only GH secretion, but also the secretion of other hormones, growth factors, and cytokines. Thus, octreotide and the delayed-release somatostatin analogs have been used to treat symptoms associated with metastatic carcinoid tumors (e.g., flushing and diarrhea) and symptoms of adenomas secreting vasoactive intestinal peptide (e.g., watery diarrhea). Octreotide also has been labeled with indium or technetium and used for diagnostic imaging of neuroendocrine tumors such as pituitary adenomas and carcinoids. Based on structure-function studies of somatostatin and its derivatives, the amino acid residues in positions 7 to 10 [FWKT] are the major determinants of biological activity. Residues W 8 and K9 appear to be essential, whereas conservative substitutions at F7 and T10 are permissible. Active somatostatin analogs retain this core segment constrained in a cyclic structure—formed either by a disulfide bond or amide linkage—that stabilizes the optimal conformation (Patel, 1999). As noted above, the endogenous peptides, somatostatin-14 and somatostatin-28, do not discriminate very well among SSTR subtypes except for SSTR5, which shows some preference for somatostatin-28. Greater selectivity is seen with some of the somatostatin analogs. For example, the octapepetides octreotide, lanreotide, and vapreotide and the hexapeptide seglitide all bind to the SSTR subtypes with the following order of selectivity: SSTR2 > SSTR5 > SSTR3 SSTR1 and SSTR4. The octapeptide analog BIM23268 exhibits modest selectivity for SSTR5, and the undecapeptide CH275 appears to bind preferentially to SSTR1 and 4 (Patel, 1999). More recently, a series of small nonpeptide agonists that exhibit a high degree of SSTR subtype-selectivity has been isolated from combinatorial chemical libraries; these compounds may lead to a new class of highly selective, orally active somatostatin mimetics. Dopamine-Receptor Agonists The dopamine-receptor agonists are described in more detail below in the section dealing with treatment of prolactinomas. Although dopamine-receptor agonists normally stimulate GH secretion, they cause a paradoxical decrease in GH secretion in some patients with acromegaly. In patients who are unwilling to take injections, the long-acting dopamine-receptor agonist cabergoline (DOSTINEX) may lower GH and IGF-1 levels into the target range. The best responses have been seen in patients whose tumors secreted both GH and prolactin. Doses used in treating acromegaly typically are considerably higher than those employed in prolactinomas. Growth Hormone Antagonists As discussed above, derivatives of GH have been developed that bind the GH receptor but do not induce the formation of receptor dimers or activate Jak/Stat signaling. One such analog, pegvisomant, is now under clinical investigation for the treatment of acromegaly. In a 12-week trial, pegvisomant significantly decreased circulating IGF-1, achieving normal levels in up to 90% of patients at higher doses and causing significant improvement in clinical parameters such as ring size, soft-tissue swelling, and excessive perspiration and fatigue (Trainer et al., 2000). Because pegvisomant differs structurally from native GH, it may induce the formation of specific antibodies that will limit its long-term efficacy. Moreover, it substantially increases GH levels and possibly may have unanticipated side effects. Finally, there are at least theoretical concerns that loss of negative feedback by both growth hormone and IGF-1 may increase the growth of GH-secreting adenomas. Thus, while its ultimate role in the management of acromegaly remains to be determined, pegvisomant represents a novel pharmacologic agent in the management of GH excess. Prolactin
As a member of the somatotropin family, prolactin is related structurally to GH and placental lactogen. The human prolactin gene on chromosome 6 encodes a 23,000-dalton polypeptide of 199 amino acids. This polypeptide has three intramolecular disulfide bonds, and a portion of secreted prolactin is glycosylated at a single asparagine residue. In circulation, dimeric and polymeric forms of prolactin also are found, as are degradation products of 16,000 or 18,000 daltons; the biological significance of these different forms is not known. Secretion Prolactin is synthesized in lactotropes. Prolactin synthesis and secretion in the fetal pituitary start in the first few weeks of gestation. Serum prolactin levels decline shortly after birth. Whereas serum prolactin levels remain low throughout life in normal males, they are elevated somewhat in normal cycling females. Prolactin levels rise markedly during pregnancy, reach a maximum at term, and decline thereafter unless the mother breast-feeds the child. In nursing mothers, prolactin secretion is stimulated by the suckling stimulus or breast manipulation, and circulating prolactin levels can rise 10- to 100-fold within 30 minutes of stimulation. This response becomes less pronounced after several months of breast-feeding, and prolactin concentrations eventually decline to prepregnancy levels. Prolactin detected in maternal and fetal blood originates from maternal and fetal pituitaries. Prolactin also is synthesized by decidual cells near the end of the luteal phase of the menstrual cycle and early in pregnancy; the latter source is responsible for the very high levels of prolactin in amniotic fluid during the first trimester. Many of the physiological factors that influence prolactin secretion are similar to those that affect GH secretion. Thus, sleep, stress, hypoglycemia, exercise, and estrogen increase the secretion of both hormones. Like other anterior pituitary hormones, prolactin is secreted in a pulsatile manner. Prolactin is unique among the anterior pituitary hormones in that hypothalamic regulation inhibits its secretion. The major regulator of prolactin secretion is dopamine, which is released by tuberoinfundibular neurons and interacts with the D2 receptor on lactotropes to inhibit secretion of prolactin (Figure 56–3). A number of putative prolactin-releasing factors have been described, including TRH, vasoactive intestinal peptide, prolactin-releasing peptide, and pituitary adenylyl cyclase-activating peptide (PACAP), but their physiological roles are unclear. Under certain pathophysiological conditions, such as severe primary hypothyroidism, persistently elevated levels of TRH can induce hyperprolactinemia and galactorrhea. Figure 56–3. Prolactin Secretion and Actions. Prolactin is the only anterior pituitary hormone for which a unique stimulatory releasing factor (PRH?) has not been identified. Thyrotropin-releasing hormone (TRH) can stimulate prolactin release, however, and dopamine can inhibit it. Prolactin affects lactation and reproductive functions but it also has varied effects on many other tissues. Prolactin is not under feedback control by peripheral hormones.
Molecular and Cellular Bases of Prolactin Action The effects of prolactin result from interactions with specific receptors that are widely distributed among a variety of cell types within many tissues (Bole-Feysot et al., 1998). Whereas prolactin binds specifically to the prolactin receptor and has no GH-like (somatotropic) activity, human GH and placental lactogen bind to the prolactin receptors and are lactogenic. The prolactin receptor is related structurally to receptors for GH and several cytokines and uses similar signaling mechanisms (see above). The prolactin receptor is encoded by a single gene located on chromosome 5. Alternative splicing of this gene gives rise to multiple forms of the receptor, including a short form of 310 amino acids, a long form of 610 amino acids, and an intermediate form of 412 amino acids. In addition, soluble isoforms lacking the transmembrane and cytoplasmic domains bind prolactin in the circulation. Like the GH receptor, the prolactin receptor lacks intrinsic tyrosine kinase activity; hormone- induced dimerization recruits and activates Jak kinases. Phosphorylation of Jak2 kinase induces phosphorylation, dimerization, and nuclear translocation of the transcription factor Stat5. Physiological Effects of Prolactin A number of hormones—including estrogens, progesterone, placental lactogen, and GH—stimulate development of the breast and prepare it for lactation. Prolactin, acting via the prolactin receptor, plays an important role in inducing growth and differentiation of the ductal and lobuloalveolar epithelium, and lactation does not occur in the absence of this hormone. During pregnancy, the high levels of estrogen and progesterone inhibit milk secretion; their declining levels after birth permit prolactin to induce lactation. Prolactin receptors also are present in many other tissues and organs, including the hypothalamus, liver, testes, ovaries, prostate, and immune system. The physiological effects of prolactin at these sites are poorly characterized. Hyperprolactinemia suppresses the hypothalamic-pituitary-gonadal axis, presumably due to inhibitory actions of prolactin on the hypothalamus and/or gonads. The elevated prolactin levels in women who are breast-feeding often suppress the normal menstrual cycle, and pathological hyperprolactinemia is a common cause of infertility in women (see below). Agents Used to Treat Syndromes of Prolactin Excess Prolactin has no therapeutic uses. 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 (
consideration, pergolide is the cheapest available dopamine-receptor agonist. It induces many of the same side effects as does bromocriptine, but it can be given once a day, starting at 0.025 mg at bedtime and increased gradually to a maximum daily dose of 0.25 mg. Cabergoline Cabergoline (DOSTINEX) is an ergot derivative with a longer half-life (approximately 65 hours) and higher affinity and selectivity for the D2 receptor than bromocriptine (approximately 4-times more potent; Verhelst et al., 1999). Cabergoline has a much lower tendency to induce nausea, although it still may cause hypotension and dizziness. In some clinical trials, cabergoline has been more effective than bromocriptine in decreasing serum prolactin in patients with hyperprolactinemia. Cabergoline has been approved by the FDA for the treatment of hyperprolactinemia, and it likely will play an increasing role in the treatment of this syndrome. As approved by the FDA, therapy is initiated at a dose of 0.25 mg twice a week; a schedule of 0.5 mg once a week also has been used. If the serum prolactin remains elevated, the dose can be increased to a maximum of 1.5 mg two or three times a week as tolerated. The dose should not be increased more often than every 4 weeks. Quinagolide Quinagolide is a nonergot D2dopamine agonist with a half-life (22 hours) intermediate between those of bromocriptine and cabergoline. Quinagolide is administered once daily at doses of 0.1 to 0.5 mg/day. It is not approved by the FDA but has been used extensively in Europe. Patients with prolactinomas who desire to become pregnant make up a special subset of hyperprolactinemic patients. In this setting, drug safety during pregnancy is an important consideration. Bromocriptine, cabergoline, and quinagolide all induce ovulation and permit most patients with prolactinomas to become pregnant without apparent detrimental effects on pregnancy or fetal development. However, experience with cabergoline and quinagolide is much less extensive than that with bromocriptine. Therefore, bromocriptine is recommended as the first-line treatment in this setting, although opinion may change with more experience with cabergoline or 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 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 glycosylated heterodimer containing a common -subunit and a distinct -subunit that confers specificity of action. While all the - subunits of this family are similar structurally, the -subunit of CG is most different, containing a carboxy-terminal extension of 30 amino acids and extra carbohydrate residues. The carbohydrate residues on the gonadotropins influence the rate of their clearance from the circulation, thus extending their serum half-lives; the residues also play a role in signal transduction at gonadotropin receptors. The human FSH gene is located at 11p13, the LH is at 19q12.32, in close proximity to at least seven CG genes, and the gene encoding the -subunit maps to chromosome 6q21-23. 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 horses—is made by syncytiotrophoblast cells of the placenta. Pituitary gonadotropin production is 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) cause 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. 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 by pituitary gonadotropes. GnRH is encoded by a gene on chromosome 8p21 and is derived by proteolytic processing of a 92–amino acid precursor peptide to produce mature GnRH, a decapeptide with blocked amino and carboxyl termini (see Table 56–3). GnRH release is intermittent and is governed by a neural pulse generator that is located in the mediobasal hypothalamus—primarily in the arcuate nucleus—and that controls the frequency and amplitude of GnRH release from neurons in the hypothalamus. Although active late in fetal life and for approximately 1 year after birth, activity of the GnRH pulse generator decreases considerably thereafter, presumably secondarily to inhibition by the CNS. Shortly before puberty, CNS inhibition
decreases and there is an increased amplitude and frequency of GnRH pulses, particularly during sleep. As puberty progresses, the GnRH pulses increase further in amplitude and frequency until the normal adult pattern is established. The intermittent release of GnRH is crucial for the proper synthesis and release of the gonadotropins, which also are released in a pulsatile manner. The continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes. The latter actions form the basis for the clinical use of long- acting GnRH analogs that suppress gonadotropin secretion (see below for further discussion). These compounds transiently increase LH and FSH secretion, but eventually desensitize gonadotropes to GnRH, thereby inhibiting gonadotropin release. Molecular and Cellular Bases of GnRH Action The GnRH receptor, a member of the family of G protein–coupled receptors, is encoded by a gene on chromosome 4q21. The binding of GnRH or GnRH agonists to GnRH receptors on the gonadotropes activates Gq11, which in turn stimulates phospholipase activity and increases the intracellular concentration of Ca2+, thereby increasing both the synthesis and secretion of LH and FSH. Although cyclic AMP is not the major mediator of GnRH action, binding of GnRH also modulates adenylyl cyclase activity. GnRH receptors also are present in the ovary and testis, although their physiological significance at these sites remains to be determined. Gonadal steroids also regulate gonadotropin production—at the level of both the pituitary and the hypothalamus—but effects on the hypothalamus predominate. The feedback effects of gonadal steroids are gender-, dosage-, and time-dependent. In women, low levels of estradiol and progesterone inhibit gonadotropin production largely through opioid action on the neural pulse generator that controls GnRH production. Higher and more sustained levels of estradiol have positive feedback effects that ultimately result in the gonadotropin surge that precedes ovulation. In men, testosterone inhibits gonadotropin production, in part through direct actions and in part after its metabolism to estradiol. Another important regulator of gonadotropin production is the gonadal peptide hormone inhibin. Inhibin is made by granulosa cells in the ovary and Sertoli cells in the testis in response to the gonadotropins and local growth factors; it acts directly in the pituitary, selectively inhibiting FSH secretion without affecting that of LH. Inhibin is structurally similar to the family of glycoproteins that includes transforming growth factor and antimüllerian hormone. Molecular and Cellular Bases of Gonadotropin Action LH and FSH were named initially based on their actions on the ovary; appreciation of their roles in male reproductive function did not come until later. The actions of LH and CG are mediated by the LH receptor (the gene for which is located on chromosome 2p21) and those of FSH are mediated by the FSH receptor (the gene for which is located on chromosome 2q). Both of these G protein– coupled receptors have large, glycosylated extracellular domains that contribute to their affinity and specificity for their ligands. The FSH and LH receptors couple with Gs to activate adenylyl cyclase and raise the intracellular level of cyclic AMP. At higher ligand concentrations, the agonist- occupied gonadotropin receptors also activate protein kinase C and Ca2+ signaling pathways via Gq- mediated effects on phospholipase C activity. Since most if not all of the actions of the gonadotropins can be mimicked by cyclic AMP analogs, the precise physiological role of Ca2+ and protein kinase C in gonadotropin action remains to be determined.
Physiological Effects of Gonadotropins In men, LH acts on testicular Leydig cells to stimulate the de novo synthesis of androgens, primarily testosterone. Testosterone is required for gametogenesis within the seminiferous tubules and for maintenance of libido and secondary sexual characteristics. FSH acts on the Sertoli cells to stimulate the production of proteins and nutrients required for sperm maturation, thereby indirectly supporting germ cell maturation. The actions of FSH and LH in women are more complicated than those in men. FSH stimulates the growth of developing ovarian follicles and induces the expression of LH receptors on both theca and granulosa cells. FSH also regulates the activity of aromatase in granulosa cells, thereby stimulating the production of 17 -estradiol. LH acts on the theca cells to stimulate the synthesis of androstenedione, the major precursor of ovarian 17 -estradiol in premenopausal women. LH also is required for the rupture of the dominant follicle during ovulation and for the synthesis of progesterone by the corpus luteum. Finally, LH and the LH receptor in women induce the expression of the FSH receptor by granulosa cells; LH thus plays a permissive role in FSH action. The essential roles of gonadotropins in reproductive physiology are revealed by human subjects with mutations of either the gonadotropin subunits or their cognate receptors (Achermann and Jameson, 1999). Women with mutations in either FSH or its receptor present clinically with primary amenorrhea, infertility, and absent breast development. Histologically, the ovarian follicles fail to mature and corpora lutea are missing. These findings, in conjunction with success in assisted reproductive technologies using FSH alone (see below), establish the critical role of FSH in ovarian function. In men, mutations of FSH or the FSH receptor are associated with decreased testis size and oligospermia, although several subjects have been fertile. The only reported inactivating mutation of LH was in a 46-year-old XY subject with Leydig cell hypoplasia, lack of spontaneous puberty, and infertility. The external genitalia were masculinized, suggesting that CG mediates androgen production in utero. In contrast, apparently complete loss-of- function mutations of the LH receptor cause phenotypes ranging from male hypogonadism to male- to-female sex reversal of the external genitalia and failure to initiate puberty. Presumably, the absence of any virilization of the external genitalia reflects combined loss of both CG and LH signaling in utero. Women with homozygous inactivating mutations of the LH receptor present with primary amenorrhea, oligoamenorrhea, or infertility and have cystic ovaries on histological examination. Mutations leading to a constitutively active LH receptor affect males primarily and are autosomal dominant. These mutations result in precocious puberty due to the uncontrolled production of testosterone in the fetal and prepubertal periods. A subset of these mutations also has been associated with testicular tumors. Diagnostic and Therapeutic Uses of GnRH and Its Analogs As illustrated in Table 56–3, a number of clinically useful GnRH analogs have been synthesized. These include synthetic GnRH (gonadorelin) and GnRH analogs that contain substitutions at position 6 that protect against proteolysis and substitutions at the C-terminus that improve receptor- binding affinity. The analogs exhibit enhanced potency and a prolonged duration of action compared to GnRH, which has a half-life of approximately 2 to 4 minutes. Pure GnRH antagonists have been developed that do not cause the initial increase in gonadotropin
secretion seen with the long-acting GnRH agonists. These newer antagonists apparently do not provoke local and systemic histamine release and the anaphylactoid reactions that hampered the clinical development of earlier analogs. Two different GnRH antagonists, ganirelix (ORGALUTRAN, ANTAGON) and cetrorelix (CETROTIDE), have been used to suppress the LH surge in ovarian- stimulation protocols that are part of assisted reproduction techniques. Ganirelix is available in the United States. Cetrorelix is available in Europe, but not in the United States. Although the almost immediate suppression of LH theoretically should result in a decreased duration of the in vitro fertilization cycle and a better-controlled regimen of ovarian stimulation (see below), more clinical trials are needed to define the roles of these compounds in assisted reproduction technologies. Diagnostic Uses Synthetic GnRH (gonadorelin hydrochloride;FACTREL) is marketed for diagnostic purposes to differentiate between pituitary and hypothalamic defects in patients with hypogonadotropic hypogonadism. After a blood sample is obtained for the baseline LH value, a single 100- g dose of GnRH is administered subcutaneously or intravenously and serum LH levels are measured over the next 2 hours (at 15, 30, 45, 60, and 120 minutes after injection). A normal LH response indicates the presence of functional pituitary gonadotropes. Inasmuch as the long-term absence of GnRH can result in a decreased responsiveness of otherwise normal gonadotropes, the absence of a response does not always indicate intrinsic pituitary disease. GnRH-stimulation testing also can be used to determine whether a subject with precocious puberty has central (i.e., GnRH-dependent) or peripheral precocious puberty. Management of Infertility Gonadorelin acetate (LUTREPULSE) is a synthetic preparation of GnRH used to treat patients with reproductive disorders secondary to GnRH deficiency or disordered secretion of GnRH. It is administered by an intravenous pump in pulses that promote a physiological cycle, starting at doses of 2.5 g per pulse every 60 to 90 minutes. If necessary, the dose can be increased to 10 g per pulse until ovulation is induced, as described in the manufacturer's manual provided with the kit. Advantages over gonadotropin therapy (see below) include a lower risk of multiple pregnancies and a decreased need to monitor plasma estrogen levels or ovarian ultrasonography. Side effects generally are minimal; the most common is local phlebitis due to the infusion device. In women, normal cycling levels of ovarian steroids can be achieved, leading to ovulation and menstruation. Because of its complexity, however, this regimen is available only in specialized centers in reproductive endocrinology (Hayes et al., 1998). Although growth of testes, appearance of normal levels of gonadal steroids, and induction of spermatogenesis can be achieved in men, GnRH therapy to induce fertility in men is not approved by the FDA, is relatively expensive, and requires that an infusion pump be worn constantly. Therefore, gonadotropins generally are preferred. The long-acting GnRH agonists also have been used in ovulation-induction protocols to suppress the endogenous preovulatory surge of LH and thus prevent premature follicular luteinization. Several treatment regimens have been developed in which the GnRH agonist is given for either short or long periods—in conjunction with gonadotropins to induce follicular maturation (see below)—and then ovulation is induced with CG (Lunenfeld, 1999). Suppression of Gonadotropin Secretion
As noted above, long-acting GnRH analogs eventually desensitize GnRH receptor-elicited signaling pathways, markedly inhibiting gonadotropin secretion and decreasing the production of gonadal steroids. This "medical castration" has proven to be very useful in disorders that respond to reductions in gonadal steroids. Perhaps the clearest indication for this therapy is in children with gonadotropin-dependent precocious puberty (also called central precocious puberty), whose premature sexual maturation can be arrested with minimal side effects by chronic administration of the GnRH agonists. Long-acting GnRH agonists are used for palliative therapy of hormonally responsive tumors (e.g., prostate or breast cancer), generally in conjunction with agents that block steroid biosynthesis or action to avoid transient increases in hormone levels. The analogs also are used to suppress steroid- responsive conditions such as endometriosis, uterine leiomyomas, and acute intermittent porphyria. Finally, depot preparations of goserelin (ZOLADEX), which can be implanted subcutaneously every 3 months (10.8 mg), may make this drug particularly useful for medical castration in disorders such as pedophilia, where strict patient supervision may be required to ensure compliance. The long-acting agonists generally are well tolerated, and side effects are those that would be predicted to occur when gonadal steroidogenesis is inhibited (e.g., hot flashes, vaginal dryness and atrophy, decreased bone density). Because of these effects, therapy in settings such as endometrioisis or uterine leiomyomas generally is limited to 6 months unless add-back therapy with estrogens is included to minimize effects on bone density. Diagnostic Uses of Gonadotropins Diagnosis of Pregnancy Significant amounts of CG are present in both the maternal bloodstream and urine during pregnancy and can be detected immunologically with antisera raised against its unique -subunit. This provides the basis for commercial pregnancy kits that qualitatively assay for the presence or absence of CG in the urine. These kits, which offer a rapid, noninvasive means of detecting pregnancy within a few days after a woman's first missed menstrual period, are available in the United States without a prescription. Quantitative measurements of CG concentration in plasma are determined by radioimmunoassay in clinical and research laboratories. These assays typically are used to assess whether or not pregnancy is proceeding normally or to help detect the presence of an ectopic pregnancy, hydatidiform mole, or choriocarcinoma. Prediction of Ovulation Ovulation occurs 36 hours after the onset of the LH surge (10 to 12 hours after the peak of LH). Therefore, urinary concentrations of LH can be used to predict the time of ovulation. Kits are commercially available without a prescription that provide a semiquantitative assessment of LH levels in urine, using LH-specific antibodies that do not recognize other gonadotropins. Urine LH levels are measured every 12 to 24 hours, beginning on day 11 of the menstrual cycle (assuming a 28-day cycle), to detect the rise in LH and thus estimate the time of ovulation. Such estimates facilitate the timing of sexual intercourse to achieve pregnancy. Diagnosis of Diseases of the Male and Female Reproductive System