Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

GHRH, Somatostatin, TRH, TSH, CRH, ACTH, GnRH, FSH, LH, & Dopamine

The receptors for these hormones are typical seven-transmembrane-domain serpentine peptides (see Chapter 2: Drug Receptors & Pharmacodynamics). Each hormone acts as a ligand within a receptor pocket, inducing conformational activating changes in the receptor. The conformational changes in the receptor's intracellular third loop and carboxyl terminal tail activate an adjacent intracellular G protein. The G14 protein is associated with the receptors for GnRH and TRH, Gi with the dopamine receptor, and Gs protein with the receptors for the other hormones listed above.

GHRH, CRH, GnRH, TSH, ACTH, FSH, LH, and Dopamine

The G protein-GTP complexes related to receptors for these hormones activate adenylyl cyclase, which synthesizes the second messenger cAMP. Cyclic AMP activates protein kinases, which phosphorylate certain intracellular proteins (eg, enzymes), thus producing the hormonal effect. Conversely, dopamine binding to lactotroph receptors causes conformational changes in its Gi protein that reduce the activity of adenylyl cyclase and inhibit the secretion of prolactin.

Somatostatin

The -GTP complexes related to somatostatin receptors exert effects on potassium channels, thereby inhibiting GH secretion.

Thyrotropin-Releasing Hormone

The G protein complexes related to thyrotrophs' TRH receptors affect phosphoinositide-specific phospholipase C, which increases intracellular cytoplasmic free calcium, thereby stimulating TSH secretion.

Growth Hormone & Prolactin

The receptors for both GH and PRL consist of similar single peptides. The two types of receptors have extracellular amino terminal hormone-binding domains. Both receptors pass through the cell membrane, where an intracellular carboxyl terminal sequence activates a tyrosine kinase, JAK2, causing phosphorylation on tyrosines of intracellular proteins and gene regulation. Fragments of GH receptors circulate in plasma (GH binding protein, GHBP), binding about 50% of the circulating growth hormone.

Growth Hormone-Releasing Hormone (GHRH) & Growth Hormone-Releasing Peptides (GHRPS)

Growth hormone-releasing hormone is a peptide hormone found in the hypothalamus that stimulates synthesis and release of growth hormone (GH) from the pituitary. It is sometimes abbreviated GRH and was originally named growth hormone-releasing factor (GRF). It was first isolated from rare pancreatic tumors that caused acromegaly by stimulating excessive GH secretion by pituitary somatotroph cells (an unusual cause—almost all cases of acromegaly are caused by pituitary tumors). In the hypothalamus, cells in the arcuate nuclei secrete GHRH into the hypophysial-pituitary portal venous system.

Chemistry & Pharmacokinetics

Structure

Naturally occurring GHRH has been isolated as both 40 and 44 amino acid peptides (GHRH40, GHRH44), which are derived from precursor molecules of 107 and 108 amino acids. GHRH bears distinct structural homologies to certain gastrointestinal peptide hormones such as gastrin, gastric inhibitory peptide, secretin, and vasoactive intestinal polypeptide. Full biologic activity of GHRH lies in the 1–29 amino terminal segment.

Growth hormone-releasing peptides comprise several groups of small synthetic peptide analogs of GHRH that can stimulate GH secretion. Sermorelin is the commercially available acetate salt of a synthetic 29-amino-acid peptide that is the amino terminal segment of GHRH. It has also been

called GRH1–29 and GHRH1–29. Sermorelin is similar to native GHRH in its ability to stimulate GH secretion. Similar peptides (GHRP-2, GHRP-6, and hexarelin, an analog of GHRP-6) also have

clinical activity.

Absorption, Metabolism, and Excretion

GHRH is not currently available commercially; in research use it may be administered intravenously, subcutaneously, or intranasally, and the relative potencies (defined as incremental growth hormone release) by these three routes are 300, 10, and 1, respectively. Intravenous GHRH (1 g/kg) has a distribution half-life of 4 minutes and an elimination half-life of 53 minutes. Subcutaneous GHRH has a similar elimination half-life but a distribution half-life of about 10 minutes. Peak serum levels of GHRH (1 g/kg) are 37 times higher after intravenous administration compared with subcutaneous injection. Sermorelin, 2 g/kg subcutaneously, reaches peak serum concentrations in 5–20 minutes; its bioavailability is 6%. The half-life of sermorelin is about 12 minutes after either subcutaneous or intravenous injection.

Clinical Pharmacology

Diagnostic Uses

GHRH is not currently available commercially. GHRH or GHRPs such as sermorelin may be given intravenously to test pituitary GH secretory capacity as part of the clinical evaluation of childhood short stature. It is used after GH deficiency has already been established by clinical criteria, including testing with conventional stimuli for GH secretion, ie, exercise, insulin-induced hypoglycemia, intravenous arginine, oral carbidopa/levodopa, and oral clonidine. In such children, a normal GH response to GHRH indicates that GH deficiency is due to hypothalamic dysfunction. A subnormal response is not diagnostic. A rise in the serum growth hormone level demonstrates the somatotrophs' ability to produce GH and predicts a favorable response to GHRH therapy.

The response of GH to GHRH can be blunted by prior treatment with octreotide, glucocorticoids, and cyclooxygenase inhibitors such as aspirin or indomethacin. GH response to GHRH is also blunted in hypothyroidism, in obesity, and in adults over 40 years of age. Exogenous growth hormone therapy should be discontinued for at least a week prior to GHRH testing.

Therapeutic Uses

Synthetic human growth hormone is now usually used for treatment of growth hormone deficiency (see below).

Sermorelin is commercially available (see above). It and other GHRH analogs, given subcutaneously, can also stimulate GH (and thereby growth) in certain GH-deficient children with short stature. Sermorelin is given only to children who have had a positive growth hormone

response to the diagnostic test and who have a bone age of less than 7.5 years (girls) or 8 years (boys). A physician experienced in its use must carefully monitor treatment. If successful in promoting growth, treatment is continued until the desired height is reached or the epiphyses have fused, whichever comes first. Children who have an inadequate response are evaluated for hypothyroidism and considered for growth hormone therapy.

Dosage

Diagnostic Use

Sermorelin may be used as a diagnostic test for pituitary GH reserve according to the following protocol: After an overnight fast, the patient has blood drawn for GH at –15 and 0 minutes; sermorelin 1 g/kg is injected intravenously, followed by a 3 mL normal saline flush of the infusion line. Blood for GH is then drawn at 15, 30, 45, and 60 minutes following the injection. Serum GH levels must reach a peak of over 2 ng/mL to be considered a positive response.

Therapeutic Use

Sermorelin is usually given subcutaneously at a dosage of 0.03 mg/kg body weight once daily at bedtime. Alternative regimens include GHRH, 2–5 g/kg subcutaneously every 6–12 hours. GHRP- 2 has been administered intranasally in doses of 5–20 g/kg. Hexarelin has clinical activity in doses of 20 g/kg intranasally.

Toxicity

Intravenous GHRH usually causes acute but transient adverse effects lasting several minutes. These effects include flushing, injection site pain and erythema, nausea, headache, metallic taste, pallor, and chest tightness.

Chronic subcutaneous GHRH therapy causes injection site reactions (pain, swelling, erythema) in about 20% of patients. Other reported adverse reactions have included headaches, flushing, dysphagia, dizziness, hyperactivity, somnolence, and urticaria.

GHRH analogs are not known to cause or stimulate malignancies, and long-term carcinogenic potential has not been studied. It is recommended that GHRH treatment be terminated if a malignancy is detected. GHRH treatment is not recommended for patients with GH deficiency due to an intracranial neoplasm.

Somatostatin (Growth Hormone-Inhibiting Hormone, Somato-Tropin Release-Inhibiting Hormone)

Somatostatin, a 14-amino-acid peptide, is found in the hypothalamus and other parts of the central nervous system. It has been sequenced (Figure 37–1) and synthesized. It inhibits growth hormone release in normal individuals. Somatostatin has also been identified in the pancreas and other sites in the gastrointestinal tract. It has been shown to inhibit the release of glucagon, insulin, and gastrin.

Figure 37–1.

Above: Amino acid sequence of somatostatin. Below: Sequence of the synthetic analog, octreotide (SMS 201-995).

Exogenously administered somatostatin is rapidly cleared from the circulation, with an initial halflife of 1–3 minutes. The kidney appears to play an important role in its metabolism and excretion.

Peptides have been synthesized that partially separate the various properties of somatostatin. A 7- aminoheptanoic acid derivative containing only four of the 14 amino acids of somatostatin has been found to block the effect of somatostatin.

Clinical Pharmacology of Octreotide (Somatostatin Analog)

Somatostatin has limited therapeutic usefulness because of its short duration of action and its multiple effects on many secretory systems. Octreotide is 45 times more potent than somatostatin in inhibiting growth hormone release but only twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic B cells, hyperglycemia rarely occurs during treatment. The greater potency of octreotide as compared with somatostatin is not due to differences in affinity for somatostatin receptors. Rather, it appears to be due to octreotide's much lower clearance and longer half-life. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer in humans than the half-life of somatostatin.

Octreotide, in doses of 50–200 g given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly; the carcinoid syndrome; gastrinoma; glucagonoma; nesidioblastosis; the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and "diabetic diarrhea." Somatostatin receptor scintigraphy, using radiolabeled octreotide, is useful in localizing neuroendocrine tumors having somatostatin receptors and helps predict the response to octreotide therapy. Octreotide is also useful for the acute control of bleeding from esophageal varices.

Octreotide acetate injectable suspension (octreotide long-acting release; Sandostatin LAR) is a slow-release formulation in which octreotide is incorporated into microspheres. It is instituted only after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. The microspheres must be carefully put into suspension and immediately injected into a gluteal muscle. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 20–40 mg. Octreotide is extremely costly.

Adverse effects of therapy include nausea with or without vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6

months of use in 20–30% of patients. However, the yearly incidence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B12 deficiency may occur with long-term use of octreotide.

Pegvisomant (Growth Hormone Receptor Antagonist)

Pegvisomant is a new GH receptor antagonist that is proving useful for the treatment of acromegaly. Pegvisomant is the polyethylene glycol (PEG) derivative of a mutant growth hormone (B2036) that has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site. This allows dimerization of the receptor but blocks the conformational changes required for signal transduction. Pegvisomant has less GH receptor antagonism than does B2036, but pegylation reduces its clearance rate and improves its overall clinical effectiveness. When pegvisomant was administered to 160 acromegalic patients subcutaneously daily for 12 months or more, serum levels of IGF-I fell into the normal range in 97% while serum levels of GH rose during treatment; two patients experienced growth of their GH-secreting pituitary tumors, and two patients developed increases in liver enzymes.

Growth Hormone (Somatotropin, GH)

Growth hormone is a peptide hormone produced by the anterior pituitary. It produces growth at open epiphyses via stimulation of insulin-like growth factor I (IGF-I, somatomedin C). It also causes lipolysis in adipose tissue and growth of skeletal muscle.

Chemistry & Pharmacokinetics

Structure

Human pituitary GH (somatotropin) is a 191-amino-acid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin and the placental hormone human chorionic somatomammotropin. Pituitary-derived GH is no longer used (see below). Animal GH is not completely homologous to human GH and is ineffective in humans.

Recombinant human growth hormone (rhGH) is the growth hormone preparation in widespread use. It is synthesized by introducing plasmids containing the gene for human growth hormone into a strain of microorganisms that synthesize rhGH, which is purified for pharmacologic use.

Somatropin has a 191-amino-acid sequence that is identical with human growth hormone. Somatrem has 192 amino acids consisting of the 191 amino acids of growth hormone plus an extra methionine residue at the amino terminal end. These preparations all appear to be equipotent.

Absorption, Metabolism, and Excretion

Circulating endogenous growth hormone has a half-life of 20–25 minutes and is predominantly cleared by the liver. Human growth hormone can be administered subcutaneously, with peak levels occurring in 2–4 hours and active blood levels persisting for 36 hours.

Somatropin injectable suspension (Nutropin Depot) is a long-acting preparation of rhGH enclosed within biodegradable microspheres. These microspheres degrade slowly after subcutaneous injection such that the rhGH is released over about 1 month.

Pharmacodynamics

Recombinant human growth hormone is equipotent with native pituitary growth hormone. The metabolic consequence of a pharmacologic dose of growth hormone is an initial insulin-like effect with increased tissue uptake of both glucose and amino acids and decreased lipolysis. Within a few hours, there is a peripheral insulin-antagonistic effect with impaired glucose uptake and increased lipolysis.

Pharmacologic doses of growth hormone cause longitudinal growth indirectly via another class of peptide hormones, the somatomedins, or insulin-like growth factors (IGFs). Growth hormone stimulates synthesis of somatomedins IGF-I and IGF-II (predominantly in growth plate cartilage and the liver); somatomedins promote uptake of sulfate into cartilage and are probably the actual mediators of the cellular processes associated with bone growth. This growth can be traced back to the molecular level, where increased incorporation of thymidine into DNA and uridine into RNA occurs (indicating cellular proliferation) along with increased conversion of proline to hydroxyproline (indicating cartilage synthesis).

Growth hormone deficiency leads to inadequate somatomedin production and short stature. Rarely, short stature may be caused by IGF-I deficiency despite high growth hormone levels (Laron dwarfism) or a lack of a pubertal surge of IGF-I (pygmies).

Clinical Pharmacology

Growth Hormone Deficiency

Genetic GH deficiency may present in the newborn with hypoglycemic seizures. Acquired GH deficiency is caused by damage to the pituitary or hypothalamus. In childhood, GH deficiency presents as short stature and adiposity. Criteria for diagnosis of growth hormone deficiency usually include (1) a growth rate below 4 cm per year and (2) the absence of a serum growth hormone response to two growth hormone secretagogues. The prevalence of congenital growth hormone deficiency is approximately 1:4000 live births.

Therapy with rhGH permits many children with short stature to achieve normal adult height.

Adults with GH deficiency tend to have generalized obesity, reduced muscle mass, asthenia, and reduced cardiac output. Adult-onset GH deficiency is usually found in the presence of other pituitary hormone deficiencies, and is usually due to damage to the hypothalamus or pituitary caused by tumor, infection, surgery, or radiation therapy.

The precise testing required to diagnose GH deficiency is controversial. Treatment of GH-deficient adults can cause increased lean body mass and bone density, decreased fat mass, increased exercise tolerance, and an improved sense of well-being. Adverse effects often include arthralgias and fluid retention.

Growth Hormone-Responsive States

Some non-growth hormone-deficient short children with a delayed bone age and a slow growth rate achieve increased growth with short-term growth hormone therapy. Selected "normal variant short stature" children can be offered a trial of growth hormone following a baseline period of measurement to confirm a subnormal growth rate. During the first 6 months of treatment, the height velocity must increase by 2 cm per year for treatment to continue. Girls with Turner's syndrome frequently respond to high-dose growth hormone therapy with increased growth velocity and increased height as adults.

In 1993, the FDA approved the use of recombinant bovine growth hormone (rbGH) in dairy cattle to increase milk production. Although milk and meat from rbGH-treated cows appears to be safe, these cows have a higher frequency of mastitis, which could increase antibiotic use and result in greater antibiotic residues in milk and meat.

Experimental Uses

Therapy with rhGH appears to be effective for infants with intrauterine growth retardation. Children with growth retardation following renal transplantation also appear to respond to rhGH therapy. Hypophosphatemia due to hyperphosphaturia (eg, X-linked hypophosphatemic vitamin D-resistant rickets) has been improved by adding rhGH to the treatment regimen.

Serum levels of growth hormone normally decline with aging. Elderly men treated with rhGH for 6 months had an increase in muscle mass and bone density and a drop of 13% in fat mass, but functional abilities remained unchanged. Available data do not support the use of rhGH to reverse the manifestations of normal aging.

Dosage

The therapeutic dosage of recombinant human growth hormone must be individualized. It is usually given in the evening by subcutaneous injection in the thighs, rotating the sites of injections. One milligram of standard rhGH preparations is equivalent to 3 units.

Children

Treatment is begun with 0.025 mg/kg daily and may be increased to a maximum of 0.045 mg/kg daily. Somatropin injectable suspension (Nutropin Depot) is a long-acting preparation of rhGH that is administered subcutaneously in doses of 1.5 mg/kg monthly or 0.75 mg/kg twice monthly. Children must be observed closely for slowing of growth velocity, which could indicate a need to increase the dosage or the possibility of epiphysial fusion or intercurrent problems such as hypothyroidism or malnutrition. Children with Turner's syndrome or chronic renal insufficiency require somewhat higher doses. The injection should be given at least 3 hours after dialysis to reduce the risk of hematoma formation due to residual heparin effect.

Adults

The required dosage for adults is lower than that for children. Treatment is begun at about 0.2 mg three times weekly and titrated upward gradually at intervals of 2–4 weeks to a maximum of 0.025 mg/kg/d (adults under age 35) or 0.0125 mg/kg/d (adults over age 35) given three to seven times weekly according to clinical response. Somatropin injectable suspension is administered subcutaneously to adult men in doses of 0.2–0.4 mg/kg every 2 weeks; it is administered to adult women taking oral estrogen in doses of 0.4–0.6 mg/kg every 2 weeks. Women usually require higher dosages than men, perhaps because of concomitant use of oral estrogens. Clinical response and adverse effects best determine the final therapeutic dosage. Serum IGF-I levels (ageand sexadjusted) can also be used.

Toxicity & Contraindications

Before 1985, GH was obtained from human cadaver pituitary glands. A small number of individuals who received cadaver-derived pooled growth hormone preparations developed Creutzfeldt-Jakob disease, a fatal neurodegenerative disease that presented many years after GH treatment. (This

disease is caused by prions, infectious proteins containing no DNA or RNA, which escaped the usual purification processes.) Distribution of pituitary-derived GH ceased in 1985. Recombinant human growth hormone carries no such risk.

Children generally tolerate GH treatment well. A rarely reported side effect is intracranial hypertension, which may present with vision changes, headache, nausea, or vomiting. Some children develop scoliosis during rapid growth. Patients with Turner's syndrome have an increased risk of otitis media while taking GH. Hypothyroidism is commonly discovered during GH treatment, so periodic assessment of thyroid function is indicated. Pancreatitis, gynecomastia, and nevus growth have occurred in patients receiving GH. Adults tend to have more adverse effects from GH therapy. Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. GH treatment increases the activity of cytochrome P450 isoforms, which could reduce the serum levels of drugs metabolized by that enzyme system (see Chapter 4: Drug Biotransformation). There has been no increased incidence of malignancy among patients receiving GH therapy, but GH treatment is contraindicated in a patient with a known malignancy. Proliferative retinopathy may rarely occur. GH treatment of critically ill patients appears to increase mortality.

Side effects of the long-acting somatropin injectable suspension have included injection-site nodules that persist for 5–7 days (96%), edema, arthralgias, transient fatigue (24%), mild-moderate nausea (24%), and headache (36%).

Thyrotropin-Releasing Hormone (Protirelin, TRH)

Thyrotropin-releasing hormone, or protirelin, is a tripeptide hormone found in the paraventricular nuclei of the hypothalamus as well as in other parts of the brain. TRH is secreted into the portal venous system and stimulates the pituitary to produce thyroid-stimulating hormone (TSH, thyrotropin), which in turn stimulates the thyroid to produce thyroxine (T4) and triiodothyronine (T3). TRH stimulation of thyrotropin is blocked by thyroxine and potentiated by lack of thyroxine.

Chemistry & Pharmacokinetics

TRH is (pyro)Glu-His-Pro-NH2. It is administered intravenously over 1 minute. Rapid plasma inactivation occurs, with a half-life of 4–5 minutes.

Pharmacodynamics

Peak serum thyrotropin levels occur 20–30 seconds after intravenous TRH injection in healthy individuals. In hyperthyroidism, the serum thyrotropin level is suppressed. In primary hypothyroidism, thyrotropin levels are high and the thyrotropin response to TRH may be accentuated. In secondary (pituitary) hypothyroidism, serum thyrotropin levels are "inappropriately" normal or low (using a sensitive TSH assay); TSH often fails to rise after TRH administration. In tertiary (hypothalamic) hypothyroidism, the baseline serum thyrotropin level may be normal or low and the thyrotropin response to TRH may be normal or blunted.

TRH infusion leads to stimulation of prolactin release by the pituitary in healthy individuals but has no effect on cells producing growth hormone or ACTH. In certain types of pituitary tumors, however, the neoplastic cells may respond abnormally to TRH by releasing growth hormone (in acromegaly), by releasing ACTH (in Cushing's disease), or by failing to release prolactin (in most prolactinomas). Infusion of TRH or TRH analogs has been reported to improve the outcome of partial spinal cord injuries.

Clinical Pharmacology

TRH testing (see above) is now rarely used to diagnose hyperthyroidism or hypothyroidism, having been supplanted by sensitive assays for serum thyrotropin (see below).

Dosage

The dose of protirelin for diagnostic use is 500 g for adults and 7 g/kg for children aged 6 years or older but not to exceed the adult dose. A baseline thyrotropin level should be obtained, followed by three further determinations at 15, 30, and 60 minutes postinfusion. The test is performed with the patient supine while blood pressure is monitored.

Toxicity

Most patients given intravenous TRH note adverse effects lasting for a few minutes: an urge to urinate, a metallic taste, nausea, flushing, or light-headedness. Transient hypertension or hypotension may occur, and marked blood pressure fluctuations have been reported in a few patients.

Thyroid-Stimulating Hormone (Thyrotropin, TSH) & Thyrotropin Alpha (rhTSH)

Thyrotropin is an anterior pituitary hormone that stimulates the thyroid to produce and synthesize thyroxine (T4), triiodothyronine (T3), and thyroglobulin. Thyrotropin alpha is a commercially available analog of TSH that is used to help detection of metastatic differentiated thyroid carcinoma; it is also known as recombinant human TSH (rhTSH).

Chemistry & Pharmacokinetics

Structure

Thyrotropin is a glycoprotein consisting of two peptide (alpha and beta) subunits joined noncovalently. The TSH-alpha subunit in humans has 89 amino acids and is virtually identical to that of the alpha subunit of FSH, LH, and hCG. The TSH-beta subunit has 112 amino acids and confers thyroid specificity. Carbohydrate side chains glycosylate each subunit prior to secretion and are important for hormone action. Native TSH is actually secreted as a mixture of glycosylation variants, having both sialylated and sulfated forms.

Thyrotropin alpha is a purified synthetic analog of native pituitary TSH that is produced in a Chinese hamster ovary cell line cotransfected with recombinant plasmids containing DNA sequences that encode the alpha and beta subunits of TSH. Like native TSH, thyrotropin alpha is a heterodimeric glycoprotein containing an alpha subunit of 92 amino acids with two glycosylation sites and a beta subunit of 118 amino acids with one glycosylation site. These subunits are slightly longer than those of pituitary TSH but contain amino acid sequences identical to those of native TSH. Like pituitary TSH, synthetic thyrotropin alpha is a mixture of glycosylated variants, but with only sialylated forms.

Absorption, Metabolism, and Excretion

Following an intramuscular injection of thyrotropin alpha (0.9 mg), the peak rhTSH concentration is reached in about 10 hours (range, 3–24 hours). The mean elimination half-life of thyrotropin alpha is 22 hours. Pituitary TSH is cleared by the kidneys and liver. Little unchanged thyrotropin is

found in the urine.

Pharmacodynamics

Thyrotropin alpha has the biologic properties of pituitary TSH. It binds to TSH receptors on both normal thyroid and differentiated thyroid cancer cells. The TSH-activated receptor stimulates intracellular adenylyl cyclase activity. Increased cAMP production causes increased iodine uptake and increased production of thyroid hormones and thyroglobulin.

Clinical Pharmacology

Diagnostic Uses

Patients with well-differentiated (papillary or follicular) thyroid carcinoma are treated with surgical resection of the cancer along with total or near-total thyroidectomy. Total thyroidectomy normally reduces the serum levels of thyroid hormones and thyroglobulin to undetectable levels.

Postoperatively, these patients must take oral thyroid hormone in order to maintain clinical euthyroidism and to suppress pituitary TSH secretion, thereby preventing any stimulation of tumor growth by TSH. Since thyroid cancer can recur years after apparent cure, such patients should have follow-up TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations. However, the aggressiveness of follow-up surveillance must be individualized according to each patient's risk of recurrence. Traditionally, patients have had to endure prolonged withdrawal of thyroid hormone replacement for many weeks before these tests in order to allow their TSH levels to rise high enough to stimulate any remaining tumor cells to resume their uptake of 131I and their secretion of thyroglobulin. The use of thyrotropin alpha can obviate the need for cessation of thyroid hormone replacement prior to the diagnostic whole-body 131I scan and serum thyroglobulin determination.

Therapeutic Uses

Treatment of metastatic differentiated thyroid cancer requires the administration of large doses of 131I (30–200 mCi) in the presence of persistently high serum levels of TSH (see Chapter 38: Thyroid & Antithyroid Drugs). Patients must withdraw from thyroid hormone replacement in order to achieve this. For treatment purposes, thyrotropin alpha administration cannot substitute for thyroid hormone withdrawal.

Dosage

Thyrotropin alpha injections can stimulate uptake of 131I by thyroid cancer or residual thyroid. The preparation is stored as a lyophilized powder that must be reconstituted before use. The dosage is 0.9 mg intragluteally (not intravenously) every 24 hours for two doses (eg, Monday and Tuesday). Twenty-four hours after the final thyrotropin injection (eg, Wednesday), 131I is administered in a dosage of at least 4 mCi (a larger dose than in hypothyroid patients, since iodine clearance is faster in euthyroid patients). Then, 48 hours after the 131I administration (eg, Friday), a serum thyroglobulin is drawn and a scan is obtained using a gamma camera, with neck, anterior whole body, and posterior whole-body imaging. If the scan shows probable metastases or if the serum thyroglobulin level (using a sensitive assay) is > 2.5 ng/mL, further evaluation and treatment are indicated.

Toxicity