Joseph K. Jordan, Amy Heck Sheehan, Jack A. Yanovski, and Karim Anton Calis
KEY CONCEPTS
Pharmacologic therapy for acromegaly should be considered when surgery and irradiation are contraindicated, when there is poor likelihood of surgical success, when rapid control of symptoms is needed, or when other treatments have failed to normalize growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations.
Pharmacotherapy for acromegaly using dopamine agonists provides advantages of oral dosing and reduced cost compared to somatostatin analogs and pegvisomant. However, dopamine agonists effectively normalize IGF-1 concentrations in only 10% of patients. Therefore, somatostatin analogs remain the mainstay of therapy.
Blood glucose concentrations should be monitored frequently in the early stages of somatostatin analog therapy in all acromegalic patients.
Pegvisomant appears to be the most effective agent for normalizing IGF-1 concentrations. However, further study is needed to determine the long-term safety and efficacy of this agent for the treatment of acromegaly.
Recombinant GH is currently considered the mainstay of therapy for treatment of children with growth hormone-deficient (GHD) short stature. Prompt diagnosis of GHD and initiation of replacement therapy with recombinant GH is crucial for optimizing final adult heights.
All GH products are generally considered to be equally efficacious. The recommended dose for treatment of GHD short stature in children is 0.3 mg/kg/wk.
Pharmacologic agents that antagonize dopamine or increase the release of prolactin can induce hyperprolactinemia. Discontinuation of the offending medication and initiation of an appropriate therapeutic alternative usually normalize serum prolactin concentrations.
Cabergoline appears to be more effective than bromocriptine for the medical management of prolactinomas and offers the advantage of less-frequent dosing and fewer adverse effects.
Although preliminary data do not suggest cabergoline has significant teratogenic potential, cabergoline is not recommended for use during pregnancy, and patients receiving cabergoline who plan to become pregnant should discontinue the medication as soon as pregnancy is detected.
Pharmacologic treatment of panhypopituitarism consists of glucocorticoids, thyroid hormone preparations, sex steroids, and recombinant GH, where appropriate, as lifelong replacement therapy.
INTRODUCTION
In the 1950s, Geoffrey Harris and his colleagues uncovered the physiologic importance of pituitary hormones and proposed the theory of neurohormonal regulation of the pituitary by the hypothalamus.1Today the pituitary gland is recognized for its essential role in body homeostasis, and for this reason it is often referred to as the “master gland.” The hypothalamus and the pituitary gland are closely connected, and together they provide a means of communication between the brain and many of the body’s endocrine organs. The hypothalamus uses nervous input and metabolic signals from the body to control the secretion of pituitary hormones that regulate growth, thyroid function, adrenal activity, reproduction, lactation, and fluid balance.
ANATOMY AND PHYSIOLOGY
The hypothalamus (Fig. 60-1) is a small region at the base of the brain that receives autonomic nervous input from different areas of the body to regulate limbic functions, food and water intake, body temperature, cardiovascular function, respiratory function, and diurnal rhythms. In addition, the hypothalamus controls the release of hormones from the anterior and posterior regions of the pituitary gland. Neurons in the hypothalamus produce vasopressin and oxytocin and make many hormone-releasing factors that stimulate or inhibit the release of trophic hormones. At the base of the hypothalamus, a projection known as the median eminence is rich with nerve axons and blood vessels and provides both chemical and physical connections between the hypothalamus and the pituitary gland.
FIGURE 60-1 Pituitary gland.
The pituitary gland, also referred to as the hypophysis, is located at the base of the brain in a cavity of the sphenoid bone known as the sellaturcica. The pituitary is separated from the brain by an extension of the dura mater known as the diaphragma sellae. The pituitary is a very small gland, weighing between 0.4 and 1 g in adults. It is divided into two distinct regions: the anterior lobe, or adenohypophysis; and the posterior lobe, or the neurohypopituitary gland.physis (see Fig. 60-1).
The posterior pituitary gland secretes two major hormones: oxytocin and vasopressin (antidiuretic hormone) (Table 60-1). Oxytocin release from the posterior pituitary causes contraction of the smooth muscles in the breast during lactation. It also plays a role in uterine contraction during parturition. Vasopressin is essential for proper fluid balance and acts on the renal collecting ducts to conserve water. Oxytocin and vasopressin are synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. The posterior pituitary gland contains the terminal nerve endings of these two nuclei as well as specialized secretory granules that release hormones in response to appropriate signals. Loss of anterior pituitary function does not necessarily affect the release of vasopressin or oxytocin because these hormones actually are synthesized in the hypothalamus.
TABLE 60-1 Pituitary Hormones
Unlike the posterior pituitary, the release of anterior pituitary hormones is not regulated by direct nervous stimulation but rather is controlled by specific hypothalamic-releasing and inhibitory hormones. The median eminence of the hypothalamus contains a large number of capillaries that converge to form a network of veins known as the hypothalamic–hypophyseal portal circulation. Inhibiting and releasing hormones synthesized in the neurons of the hypothalamus reach the anterior pituitary via the hypothalamic–hypophyseal portal vessels to control release of anterior pituitary hormones. Although there is a direct arterial blood supply to the anterior pituitary lobe, the hypothalamic–hypophyseal portal vessels provide the primary blood supply (see Fig. 60-1). In contrast to the posterior pituitary, the anterior pituitary lobe is extremely vascular and has the highest rate of blood flow of all body organs.
The specialized secretory cells of the anterior pituitary lobe secrete six major polypeptide hormones (see Table 60-1). These include growth hormone (GH) or somatotropin, adrenocorticotropic hormone (ACTH) or corticotropin, thyroid-stimulating hormone (TSH) or thyrotropin, prolactin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The release of these hormones is regulated primarily by hypothalamic-releasing and inhibiting hormones. Thyrotropin-releasing hormone (TRH) stimulates anterior pituitary release of TSH and prolactin, corticotropin-releasing hormone (CRH) stimulates anterior pituitary release of ACTH, growth hormone-releasing hormone (GHRH) stimulates anterior pituitary release of GH, and gonadotropin-releasing hormone (GnRH) stimulates anterior pituitary release of LH and FSH. Hypothalamic release of somatostatin inhibits release of GH, and hypothalamic release of dopamine (prolactin inhibitory hormone) inhibits the secretion of prolactin. Prolactin differs from the other anterior lobe hormones in that an inhibiting factor, rather than a stimulating factor, is primarily responsible for controlling its secretion. In the absence of hypothalamic input, an excess of prolactin is produced, whereas a deficiency state of other anterior pituitary hormones results. Physiologic regulation and action of anterior and posterior pituitary hormones are summarized in Table 60-1.2–4
Destruction of the pituitary gland may result in secondary hypothyroidism, hypogonadism, adrenal insufficiency, GH deficiency, and hypoprolactinemia. The formation of certain types of pituitary tumors may result in pituitary hormone excess. Pituitary tumors may physically compress the pituitary and prevent the release of trophic hypothalamic factors that regulate pituitary hormones. In this chapter, the pathophysiology and role of pharmacotherapy in the treatment of acromegaly, short stature, hyperprolactinemia, and panhypopituitarism are discussed.
GROWTH HORMONE
GH has direct antiinsulin effects on lipid and carbohydrate metabolism. GH decreases utilization of glucose by peripheral tissues, increases lipolysis, and increases muscle mass. GH also stimulates gluconeogenesis in hepatocytes, impairs tissue glucose uptake, decreases insulin-receptor sensitivity, and impairs postreceptor insulin action. The growth-promoting effects of GH are largely mediated by insulin-like growth factors (IGFs) also known as somatomedins. GH stimulates the formation of IGF-1 in the liver as well as in other peripheral tissues. This anabolic peptide acts as a direct stimulator of cell proliferation and growth. There are two types of IGFs: IGF-1 and IGF-2. IGF-1 regulates growth to some extent before, and largely after, birth. In contrast, IGF-2 is thought to primarily regulate growth in utero.5 GH is secreted by the anterior pituitary in a pulsatile fashion, with several short bursts that occur mostly at night. Because of the short half-life of GH in the plasma (~30 minutes), measurements of circulating GH concentrations throughout the waking hours usually are very low or undetectable. Daytime GH pulses are most likely to occur after meals, following exercise, or during periods of stress. The greatest amount of GH secretion occurs during the night within the first 1 to 2 hours of slow-wave sleep (stage III or IV). Secretion of GH is lowest during infancy, increases slightly during childhood, reaches its peak during adolescence, and then begins to gradually decline during the middle-age years.3
Growth Hormone Excess
Acromegaly is a pathologic condition characterized by excessive production of GH. This is a rare disorder that affects approximately 50 to 70 adults per million.6 Gigantism, which is even more rare than acromegaly, is the excess secretion of GH prior to epiphyseal closure in children.7 Patients diagnosed with acromegaly are reported to have a two- to threefold increase in mortality, usually related to cardiovascular, respiratory, or neoplastic disease.8–10 Most patients are middle-aged at the time of diagnosis, and this disorder does not appear to affect one sex to a greater extent than the other. The most common cause of excess GH secretion in acromegaly is a GH-secreting pituitary adenoma, accounting for over 90% of all cases.8 Rarely, acromegaly is caused by ectopic GH-secreting adenomas, GH cell hyperplasia, or excess GHRH secretion, or is one of the manifestations of multiple endocrine neoplasia syndrome type 1, McCune–Albright’s syndrome, or the Carney complex, all very rare hypersecretory endocrinopathies.8
The clinical signs and symptoms of acromegaly develop gradually over an extended period of time. In fact, because of the subtle and slowly developing changes in physical appearance caused by GH excess, most patients are not definitively diagnosed with acromegaly until 7 to 10 years after the presumed onset of excessive GH secretion.9 Excessive secretion of GH and IGF-1 adversely affects several organ systems. Almost all acromegalic patients will present with physical signs and symptoms of soft-tissue overgrowth. Table 60-2 summarizes the classic clinical presentation of patients with acromegaly.8–13Some patients with acromegaly present with only a few of these classic signs and symptoms, making recognition of this disease extremely difficult.
TABLE 60-2 Clinical Presentation of Acromegaly
The diagnosis of acromegaly is based on a combination of diagnostic tests and clinical signs and symptoms. Random measures of plasma GH levels are not usually dependable because of the pulsatile pattern of release. However, some clinicians exclude diagnosis of acromegaly in the presence of a random GH <0.4 mcg/L (<18 pmol/L) and IGF-1 that is normal for age and sex.8 The oral glucose tolerance test (OGTT) is commonly used as an important diagnostic tool. Postprandial hyperglycemia inhibits the secretion of GH for at least 1 to 2 hours. Therefore, an oral glucose load would be expected to suppress GH concentrations. However, patients with acromegaly continue to secrete GH during the OGTT. Because GH stimulates the production of IGF-1, serum IGF-1 concentrations can also be measured to aid in the diagnosis of acromegaly. Circulating IGF-1 is cleared from the body at a much slower rate than is GH, and measurements can be collected at any time of the day to identify patients with GH excess.9 Current criteria for the diagnosis of acromegaly include failure of GH suppression <1 mcg/L (<45 pmol/L) following an OGTT in the presence of elevated IGF-1 serum concentrations.8,14 With the development of more sensitive GH and IGF-1 assays, the American Association of Clinical Endocrinologists (AACE) suggests lowering the cutoff for GH suppression to <0.4 mcg/L (<18 pmol/L). Insulin-like growth factor 1 binding protein 3 (IGFBP-3) also can be measured because it is positively regulated by GH and binds to circulating IGF-1 with high affinity. This test may prove useful in the future in monitoring response to therapy but, at present, AACE does not recommend IGFBP-3 measurement for the purpose of clinical management.8 Computed tomography and magnetic resonance imaging of the pituitary are important diagnostic tests to confirm the presence of a pituitary adenoma.8,14
TREATMENT
Acromegaly
The primary treatment goals for patients diagnosed with acromegaly are to reduce GH and IGF-1 concentrations, improve the clinical signs and symptoms of the disease, and decrease mortality.8,15–17 Many clinicians define biochemical control of acromegaly as suppression of GH concentrations to <1 mcg/L (<45 pmol/L) after a standard OGTT in the presence of normal IGF-1 serum concentrations, although some argue for a lower cutoff GH value of 0.4 mcg/L (18 pmol/L) due to the availability of more sensitive test methods.16 The treatment of choice for most patients with acromegaly is transsphenoidal surgical resection of the GH-secreting adenoma.9,15,16 Postsurgical cure rates have been reported to range from 50% to 90%, depending on the type of adenoma and the expertise of the neurosurgeon.8,16,17Complications of transsphenoidal surgery are relatively infrequent and include cerebrospinal fluid leak, meningitis, arachnoiditis, diabetes insipidus, and pituitary failure.8 For patients who are poor surgical candidates, those who have not responded to surgical or medical interventions, or others who refuse surgical or medical treatment, radiation therapy may be considered. Radiation, however, may require several years to relieve the symptoms of acromegaly.
Because neither radiation therapy nor surgery will cure all patients with acromegaly, adjuvant drug therapy is often needed to control symptoms.9,17,18
Pharmacologic Therapy
Drug therapy should be considered as primary therapy for acromegalic patients who prefer medical therapy, are poor surgical candidates, or when there is a poor likelihood of surgical success. Drug therapy should be considered as adjunctive therapy in the presence of persistent disease after surgery.8 Pharmacologic treatment options include dopamine agonists, somatostatin analogs, and the GH receptor antagonist pegvisomant. Dopamine agonists such as bromocriptine and cabergoline are effective in a small subset of patients and provide the advantages of oral dosing and reduced cost. Somatostatin analogs are more effective than dopamine agonists, reducing GH concentrations and normalizing IGF-1 in approximately 50% to 60% of patients. Pegvisomant, a GH receptor antagonist, is highly effective in normalizing IGF-1 concentrations in up to 97% of patients in the first year and in 60% over 5 years.
Dopamine Agonists
In normal healthy adults, dopamine agonists cause an increase in GH production. However, when these agents are given to patients with acromegaly, there is a paradoxical decrease in GH production. Most clinical experience with the use of dopamine agonists in acromegaly is with bromocriptine or cabergoline. Other agents such as pergolide, quinagolide, and lisuride also have been used but are not available in the United States. Bromocriptine and cabergoline are semisynthetic ergot alkaloids that act as dopamine-receptor agonists. Most trials assessing the efficacy of bromocriptine in the treatment of acromegaly were conducted in the 1970s and early 1980s and determined that certain subsets of acromegalic patients with high circulating concentrations of prolactin have a favorable response to drug therapy with bromocriptine.19 A review evaluating 34 studies concluded that therapy with bromocriptine was effective in suppressing mean serum GH levels to <5 mcg/L (<225 pmol/L) in approximately 20% of patients.20 While only 10% of patients experience normalization of IGF-1 concentrations with bromocriptine therapy, greater than 50% of patients treated with bromocriptine experience improvement in symptoms of acromegaly.8,19 According to AACE guidelines, cabergoline appears used more commonly than bromocriptine. A recent meta-analysis of 15 studies concluded that cabergoline as monotherapy was effective in normalizing IGF-1 levels in 34% of patients and resulted normalization of IGF-1 levels in 52% of patients when added to a somatostatin analog in those unresponsive to somatostatin analog monotherapy.21
In the United States, bromocriptine is commercially available as 0.8 and 2.5-mg oral tablets and 5-mg oral capsules. The 0.8-mg tablet is indicated as adjunctive therapy in type 2 diabetes mellitus. In acromegalic patients, significant reductions in GH concentrations are observed within 1 to 2 hours of oral dosing. This effect persists for at least 4 to 5 hours. An overall clinical response in acromegalic patients typically occurs after 4 to 8 weeks of continuous bromocriptine therapy. For treatment of acromegaly, bromocriptine is initiated at a dose of 1.25 mg (1/2 of a 2.5-mg tablet) at bedtime and is increased by 1.25-mg increments every 3 to 4 days as needed. Doses as high as 86 mg/day have been used for treatment of acromegaly, but clinical studies have shown that dosages >20 or 30 mg daily do not offer additional benefits in the suppression of GH. When used for treatment of acromegaly, the duration of action of bromocriptine is shorter than that for treatment of hyperprolactinemia. Therefore, the total daily dose of bromocriptine should be divided into three or four doses.
Cabergoline is commercially available as 0.5 mg tablets. Use in acromegaly is considered off-label, and dosing is typically initiated at 0.5 mg twice weekly and increased as needed to 0.5 mg every other day. Doses up to 7 mg/wk (0.5 mg twice daily) have been reported in trials.
The most common adverse effects of dopamine agonist therapy include CNS symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue. GI effects such as nausea, abdominal pain, or diarrhea also are very common. Some patients may need to take dopamine agonists with food to decrease the incidence of adverse GI effects. Most adverse effects are seen early in the course of therapy and tend to decrease with continued treatment.8,19Dopamine agonists may cause thickening of bronchial secretions and nasal congestion. Rare cases of psychiatric disturbances, pleural diseases, and an erythromelalgic syndrome (painful paroxysmal dilation of the blood vessels in the skin of the feet and lower extremities) have been reported with dopamine agonist use. These conditions appear to be associated with higher doses and prolonged duration of therapy.8,19
Dopamine agonists are not FDA-approved for use during pregnancy. However, surveillance of women who took dopamine agonists throughout pregnancy does not suggest that dopamine agonists are associated with an increased risk for birth defects.22 If a woman becomes pregnant while taking dopamine agonists, the risks and benefits of therapy should be fully considered. In most cases, the benefits of successful therapy outweigh the risks, and dopamine agonist therapy should be continued if it is effective in improving symptoms and reducing elevated GH concentrations.
Other dopamine agonists that have been used to treat acromegaly include pergolide, lisuride, and quinagolide. Pergolide is no longer commercially available, and lisuride and quinagolide are not commercially available in the United States. Because of the potential cost advantages and convenience of oral administration, dopamine agonists are often considered for treatment of acromegaly prior to initiation of somatostatin analogs. However, the availability of long-acting somatostatin analogs has made these agents more attractive for first-line treatment of acromegaly.
Somatostatin Analogs
Octreotide and lanreotide are long-acting somatostatin analogs that are more potent in inhibiting GH secretion than endogenous somatostatin.23,24 These agents also suppress the LH response to GnRH; decrease splanchnic blood flow; and inhibit secretion of insulin, vasoactive intestinal peptide (VIP), gastrin, secretin, motilin, serotonin, and pancreatic polypeptide. Pasireotide is a somatostatin analog that has a broader affinity for somatostatin receptor subtypes than octreotide or lanreotide. The binding to additional subtypes of somatostatin receptors may result in greater GH inhibition compared to octreotide or lanreotide and efficacy of pasireotide in the presence of octreotide or lanreotide-resistant adenomas.23
Octreotide (Sandostatin) injection is commercially available in the United States for subcutaneous or IV administration. A long-acting intramuscular formulation of octreotide (Sandostatin LAR) is available for monthly administration. In addition to the treatment of acromegaly, octreotide has many other therapeutic uses, including the treatment of carcinoid tumors, vasoactive intestinal peptide-secreting tumors (VIPomas), GI fistulas, variceal bleeding, diarrheal states, and irritable bowel syndrome.
The efficacy of octreotide for treatment of acromegaly has been determined by two major multicenter trials.25,26 These studies determined that drug therapy with octreotide suppresses mean serum GH concentrations to <5 mcg/L (<225 pmol/L) and normalizes serum IGF-1 concentrations in 50% to 60% of acromegalic patients. Octreotide also is beneficial in reducing the clinical signs and symptoms of acromegaly. In a 6-month multicenter trial, 70% of patients experienced significant relief of headaches.26 In some patients, relief of headache symptoms occurred within minutes of octreotide administration. In addition, middle-finger circumference was reduced significantly, and 50% to 75% of patients experienced improvement in symptoms of excessive perspiration, fatigue, joint pain, and cystic acne. Long-term follow-up of patients treated with octreotide LAR for up to 9 years showed octreotide therapy to be safe and effective for long-term use in acromegalic patients.27 Octreotide also has been shown to improve the cardiovascular manifestations of acromegaly and to halt pituitary tumor growth, with some patients experiencing tumor regression.25–28 Data from more recent studies indicate that shrinkage of pituitary tumor mass during octreotide therapy occurs in approximately 50% of patients.29
The pharmacodynamic effects of long-acting octreotide are similar to those of subcutaneously administered octreotide. Single monthly doses of long-acting octreotide have been shown to be at least as effective as daily doses of subcutaneous octreotide administered in divided doses three times daily in normalizing IGF-1 levels and maintaining suppression of mean serum GH concentrations.30 Trials evaluating the efficacy of long-acting octreotide in acromegalic patients who previously had responded to subcutaneously administered octreotide have reported sustained suppression of GH concentrations to <5 mcg/L (<225 pmol/L) and normalization of IGF-1 in patients following 1 year of therapy.31
Response to long-term therapy with octreotide is related to the presence and increased quantity of functioning somatostatin receptors located in the pituitary adenoma. Identification of patients who most likely will respond to octreotide, prior to initiation of therapy, is important when considering the high cost of this medication and the inconvenience of subcutaneous or intramuscular drug administration. Suppression of serum GH concentrations after a single 50-mcg dose of octreotide has been used to predict a favorable long-term response to octreotide therapy.32,33
The initial dose of octreotide for treatment of acromegaly is usually 100 mcg administered three times daily followed by either titration to a maximum of 1500 mcg/day or transition to long-acting octreotide.8,23,24 Some clinicians recommend a starting dose of 50 mcg every 8 hours, then increasing the dose to 100 mcg every 8 hours after 1 week, to improve the patient’s tolerance of adverse GI effects. The dose can be increased by increments of 50 mcg every 1 to 2 weeks based on mean serum GH and IGF-1 concentrations. Patients who experience a significant rise in GH prior to the end of the 8-hour dosing interval may benefit from decreasing the dosing interval to every 4 to 6 hours. Although doses as high as 1,500 mcg/day have been used, doses >600 mcg daily generally do not offer additional benefits, and most patients are adequately managed with 100 to 200 mcg three times daily.8,24 Patients who have been maintained on subcutaneous octreotide for at least 2 weeks and have shown response to therapy can be converted to the long-acting depot form of octreotide. The initial dose of long-acting octreotide is 20 mg administered intramuscularly in the gluteal region every 28 days. Steady-state serum concentrations are not obtained until after 3 months of therapy. Therefore, dosage adjustments for long-acting octreotide should not be considered until after this time. Some patients may require additional subcutaneous injections during the initial dose-titration phase in order to control symptoms. In patients who achieve >50% reduction in GH levels to 30 mg every 4 weeks, some may have added response to a higher-dose regimen of 60 mg every 4 weeks.34
A long-acting, intramuscular formulation of lanreotide (lanreotide LA) for twice monthly administration has been available in Europe for many years. In 2007, a new formulation of lanreotide (Somatuline Depot) was approved for use in the United States for monthly deep subcutaneous administration. The efficacy of this preparation of lanreotide for the treatment of acromegaly has been evaluated in several prospective multicenter clinical trials involving treatment-experienced patients who were switched from intramuscular octreotide LAR or intramuscular lanreotide LA to monthly deep subcutaneous lanreotide.35,36 These studies have determined that deep subcutaneous lanreotide suppresses mean serum GH concentrations to <5 mcg/L (<225 pmol/L) and normalizes serum IGF-1 concentrations in acromegalic patients to a similar extent as octreotide LAR and lanreotide LA. A 4-year follow-up of 23 patients treated with monthly deep subcutaneous lanreotide reported the drug to be well tolerated during long-term therapy with mean serum GH concentrations <5 mcg/L (225 pmol/L) in 62% of patients and normalization of serum IGF-1 concentrations in 43% of patients.37 Analyses of trials investigating the effects of lanreotide on pituitary tumor mass have shown shrinkage in 66% to 77% of patients.35 Well-designed trials directly comparing the efficacy of intramuscular octreotide LAR to deep subcutaneous lanreotide are currently lacking. However, these two agents are generally regarded to have comparable efficacy.8
Lanreotide (Somatuline Depot) is commercially available in the United States as 60-, 90-, and 120-mg prefilled syringes. In contrast to octreotide LAR, lanreotide injection does not need to be reconstituted prior to administration. The initial recommended dose of lanreotide is 90 mg given by deep subcutaneous injection in the superior external quadrant of the buttock every 28 days. Injection sites should be alternated between the left and right side. The initial dose should be reduced to 60 mg every 28 days for patients with moderate or severe renal or hepatic impairment. After 3 months of therapy, the dose may then be titrated based on serum GH concentrations, serum IGF-1 concentrations, and control of clinical signs and symptoms of acromegaly.36 Long-acting deep subcutaneous lanreotide injection in doses >120 mg every 28 days has not been studied.
The most common adverse effects of somatostatin analog therapy are GI disturbances such as diarrhea, nausea, abdominal cramps, malabsorption of fat, and flatulence.16,23 GI adverse effects occur in approximately 75% of patients but usually subside within 10 to 14 days of continued treatment.23 Octreotide has been reported to cause injection-site pain (4% to 31%), conduction abnormalities and arrhythmias (9%), subclinical hypothyroidism (2% to 12%), biliary tract disorders (4% to 50%), and abnormalities in glucose metabolism (2% to 18%).20,23 Lanreotide has been reported to cause injection-site reactions (9%), sinus bradycardia (3%), hypertension (5%), biliary tract disorders (20%), and abnormalities in glucose metabolism (7%).36
Somatostatin analogs also inhibit cholecystokinin release and gallbladder motility, predisposing patients to the development of cholelithiasis.23 The development of gallstones is a long-term adverse effect of somatostatin analog therapy and is largely dependent on geographic factors, dietary habits, and length of therapy.20,24 The incidence of gallstones in acromegalic patients receiving octreotide and lanreotide increases with length of therapy and has been reported to range from 20% to 50%.24–26 However, most patients are asymptomatic, and the diagnosis of cholelithiasis usually is made following an ultrasonographic study that is not prompted by patient symptoms. It has been estimated that only 1% of patients will develop symptomatic gallstones during 1 year of octreotide treatment.24 Because somatostatin analog-induced gallstones usually are present without clinical symptoms, prophylactic cholecystectomy or medical therapy with ursodeoxycholic acid for acromegalic patients with asymptomatic gallstones usually is not recommended.9,16 A small number of studies have suggested that the incidence of gallstone development may be lower with long-acting octreotide compared to subcutaneous octreotide.30,31 However, further studies are needed to confirm this observation.
The effect of somatostatin analogs on glucose metabolism in patients with acromegaly is multifactorial. Decreases in serum GH concentrations induced by somatostatin analogs should result in decreased hepatic gluconeogenesis and increased insulin-receptor sensitivity. However, somatostatin analogs also decrease insulin secretion and increase IGFBP-1, which is known to inhibit the insulin-like effects of IGF-1. In addition, somatostatin analogs delay the GI absorption of glucose, which may further alter glucose metabolism in acromegalic patients.38 Small studies conducted in acromegalic patients receiving octreotide have reported improvement in insulin sensitivity as well as impaired insulin secretion.39 Risk factors associated with worsening glucose tolerance included female sex and elevated baseline insulin values. Although somatostatin analogs appear to have a beneficial effect on glucose tolerance in most patients, glucose determinations should be obtained frequently in the early stages of therapy in all acromegalic patients.
Growth Hormone Receptor Antagonist
Pegvisomant (Somavert) is a genetically engineered GH derivative that binds to, but does not activate, GH receptors and inhibits IGF-1 production. This agent is different from other medications used in the management of acromegaly because it does not inhibit GH production; rather, it blocks the physiologic effects of GH on target tissues. Therefore, GH concentrations remain elevated during therapy, and response to treatment is evidenced by a reduction in IGF-1 concentrations. Unlike somatostatin analogs, the pharmacologic activity of pegvisomant does not depend on the presence and quantity of somatostatin receptors in the pituitary tumor.40 Studies evaluating the clinical efficacy of pegvisomant in acromegalic patients have reported a dose-dependent normalization of IGF-1 concentrations in 54% to 89% of patients after 12 weeks of therapy and in 97% of patients after 1 year of therapy.40,41Significant improvements in the clinical signs and symptoms of acromegaly were reported and persisted throughout the 1-year treatment period.41 An ongoing, international post-marketing surveillance registry (ACROSTUDY) has recently reported 5-year data in patients treated with pegvisomant. In patients who predominantly had failed prior medical or surgical therapy, IGF-1 normalized in 63%. Investigators note that failure to maintain IGF-1 normalization may reflect suboptimal dosing strategies or more advanced disease than reported in the original studies.42
Adverse effects include injection-site pain, GI complaints such as nausea and diarrhea, and flu-like symptoms. Significant elevations in hepatic aminotransferase concentrations, which are generally reversible upon discontinuation of the drug, have been reported in approximately 25% of patients.43 As a result, hepatic function tests should be monitored very closely during therapy as outlined in the product labeling, and the drug should be used with caution in patients with baseline elevations in hepatic aminotransferase concentrations. GH concentrations may increase significantly during the first 6 months of therapy. Tumor growth has been reported in a small number of patients and there are theoretical concerns that the lack of GH feedback regulation on tumors that lead to persistently elevated GH concentrations may stimulate tumor growth or result in other long-term adverse effects. Interim results of the ongoing ACROSTUDY suggest that the rate of tumor growth of 3.2% is comparable to the background rate in acromegaly, and the incidence of hepatic aminotransferases greater than three times upper limit of normal is low (2.5%).43
Pegvisomant is commercially available in the United States for daily subcutaneous use. The first dose should be administered under the supervision of a physician as a 40-mg loading dose. Subsequent doses are self-administered by the patient starting at a dose of 10 mg daily. The dose can be adjusted in 5-mg increments based on serum IGF-1 concentrations every 4 to 6 weeks.43
Based on the available data, pegvisomant appears to be among the most effective agents for normalizing IGF-1 serum concentrations. Current guidelines for acromegaly management suggest pegvisomant therapy for patients who have failed to achieve normalization of IGF-1 serum concentrations with other treatments.8
Combination Therapy
Several small studies have suggested that combination therapy with somatostatin analogs, dopamine agonists, or pegvisomant may be more beneficial than monotherapy with either drug alone.8,21,44 Several of these trials have used doses lower than those typically used for monotherapy in order to try to minimize the risk of additive adverse effects. Because of the potential for additive adverse effects, combination therapy should be considered as a therapeutic option only for refractory patients who have not fully responded to monotherapy.8
Personalized Pharmacotherapy
The genetics of growth hormone and receptors have been well-studied.45 At this time, the data are most abundant with pegvisomant. As pegvisomant acts at the growth hormone receptor, researchers have investigated response to GH receptor variants. In patients with exon 3-deleted GH receptors, lower doses and fewer months were needed to obtain IGF-1 normalization.46 However, recommendations regarding how therapy can be individualized to maximize patient benefit are not yet available.8
Clinical Controversy…
Some clinicians advocate the use of somatostatin analogs prior to surgery in order to improve comorbidities that may complicate surgery. However, sufficient evidence is lacking.
Conclusions
Acromegaly is a chronic debilitating disease characterized by excess GH secretion most commonly caused by a GH-secreting pituitary adenoma. Transsphenoidal surgical resection of the adenoma is the current treatment of choice for most patients with acromegaly. Patients who are poor surgical candidates may receive radiation therapy or long-term pharmacologic therapy. Drug therapy options within the United States for acromegaly include dopamine agonists, somatostatin analogs, and pegvisomant. Figure 60-2 shows a treatment algorithm for the management of acromegaly.8,9
FIGURE 60-2 Treatment algorithm for acromegaly. (SRL, somatostatin analog; MRI, magnetic resonance imaging.) (Modified from Melmed S, Calao A, Barkan A, et al. Guidelines for acromegaly management: An update. J Clin Endocrinol Metab 2009;94:1509–1517. Copyright 2009, The Endocrine Society.)
Growth Hormone Deficiency
Short stature is a condition that is commonly defined by a physical height that is more than two standard deviations below the population mean and lower than the third percentile for height in a specific age group.47 It has been estimated that more than 1.8 million children in the United States can be characterized as having short stature.47 Short stature is a very broad term describing a condition that may be the result of many different causes. A true lack of GH is among the least common causes and is known as growth hormone-deficient (GHD) short stature. Absolute GH deficiency is a congenital disorder that can result from various genetic abnormalities, such as GHRH deficiency, GH gene deletion, and developmental disorders including pituitary aplasia or hypoplasia.47 GH insufficiency is an acquired condition that can result from hypothalamic or pituitary tumors (or their neurosurgical treatment), cranial irradiation, head trauma, pituitary infarction, and various types of CNS infections. In addition, psychosocial deprivation, hypothyroidism, poorly controlled diabetes mellitus, treatment of precocious puberty with LH-releasing hormone agonists, and pharmacologic agents such as glucocorticoids, methylphenidate, and dextroamphetamine may induce transient GH insufficiency.47
Short stature also occurs with several conditions that are not associated with a true GH deficiency or insufficiency. These conditions include intrauterine growth restriction; constitutional growth delay; malnutrition; malabsorption of nutrients associated with inflammatory bowel disease, celiac disease, and cystic fibrosis; chronic renal failure; skeletal and cartilage dysplasia; and genetic syndromes such as Turner’s syndrome.47,48 In addition, many children are diagnosed with idiopathic or normal variant short stature. These patients have heights that are significantly lower than the third percentile but present with normal GH serum concentrations and no specific underlying explanation for short stature.48
Children with congenital GHD usually are born with an average birth weight. Decreases in growth velocity generally become evident between the ages of 6 months and 3 years.47 In contrast, GH insufficiency may arise at any age during growth and development. The clinical characteristics of GHD or GH-insufficient children are listed in Table 60-3.47
TABLE 60-3 Clinical Presentation of Short Stature
Several factors must be considered in the diagnosis of GH deficiency or insufficiency. Standard epidemiologic growth charts developed by the National Center for Health Statistics typically are used to determine the percentile of anthropometric measurements, such as height, weight, and head circumference. Pubertal stage typically is determined using the Tanner method. Bone age is determined according to published standards, and growth velocity is calculated to determine the patient’s height velocity percentile using standard growth-velocity charts.47,48 GH deficiency is rarely seen in the absence of delayed skeletal maturation and decreased growth velocity. In addition, several different provocative stimuli that induce GH secretion may be used diagnostically to determine GH status. Common provocative pharmacologic GH stimuli include insulin-induced hypoglycemia, clonidine, L-dopa, arginine, glucagon, and GHRH.47 A subnormal GH response during childhood is arbitrarily defined as a peak GH serum concentration <10 mcg/L (<450 pmol/L) during a 2-hour period after administration of one of these agents.47 However, this maximum may be lower, depending on the specific assay and GH reference product used. For prepubertal and early pubertal patients (Tanner stage less than III), priming with sex hormones to improve the specificity of GH provocation tests is often considered. Some patients exhibit clinical signs of GH deficiency, subnormal growth velocity, and delayed bone age despite GH levels that are within normal limits after provocative testing. This makes diagnosis in this group of patients very difficult. Diagnosis based on GH stimulation tests becomes further complicated because of the paucity of data reporting the normal range of GH concentrations after provocative testing in healthy children and the fact that commercial GH and IGF-1 assays currently available may not be equivalent. Although a gold standard for diagnosis of GHD does not exist, treatment is generally recommended for children who have “idiopathic short stature” and pass GH provocative testing but have most of the following criteria: height greater than 2.25 standard deviations below the mean for age; subnormal growth velocity; delayed bone age; low serum IGF-1 and/or insulin-like growth factor binding protein 3 (IGFBP-3); and other clinical features consistent with GH deficiency.49 Ultimately, careful consideration of multiple factors by a pediatric endocrinology specialist is required to correctly diagnose GH deficiency. Of note, more than half of children diagnosed with GH deficiency are found to secrete normal quantities of GH and IGF-1 in adulthood.50
TREATMENT
Growth Hormone Deficiency
Pharmacologic Therapy
The treatment of GH deficiency with pituitary-derived human GH was first reported in the late 1950s. The National Hormone and Pituitary Program was founded by the National Institutes of Health in 1963 to coordinate the collection of human pituitary glands and purification of GH for administration to children with GH deficiency. In 1985, three deaths linked to Creutzfeldt–Jakob disease (CJD) were identified in young individuals who were previously treated with human pituitary GH. An evaluation of National Hormone and Pituitary Program data identified 26 cases of fatal CJD in a cohort of 6,107 patients who received treatment with human pituitary-derived GH in the United States between 1963 and 1985.51 Cadaveric pituitary GH was withdrawn from the US market because of the strong likelihood that CJD was transmitted through contaminated human pituitary-derived hormone. Shortly after the withdrawal of human pituitary GH, the FDA approved the first recombinant DNA-derived GH for treatment of GH insufficiency. Prior to the introduction of recombinant GH, the number of individuals who received treatment for GH insufficiency was relatively small because of the limited availability of human pituitary tissue for GH extraction. Currently, with the widespread availability of recombinant GH products, a large number of children can receive GH replacement therapy at higher doses.
Clinical Controversy…
Many pediatric endocrinologists in the United States believe that GH therapy is appropriate treatment in certain patients with non-GHD short stature. However, given the high cost of therapy and small increases in height, use of GH in this patient population remains controversial.
Recombinant Growth Hormone
Recombinant GH is currently considered the mainstay of therapy for treatment of GHD short stature. GH replacement therapy in children with documented GHD short stature produces a significant improvement in growth velocity within the first year of therapy and significantly improves final adult height.52–55 The initial increase in growth velocity often is referred to as catch-up growth. Most of the initial studies evaluating the efficacy of GH therapy in GHD children were conducted for short periods of time in small numbers of patients, and, until recently, information about the long-term outcome of GH therapy was limited. Initial data suggested that final adult height is not substantially improved, with an average final adult height reported to be two standard deviations below the population mean.56–59Although these results were disappointing, it is important to note that a substantial percentage of patients included in these studies initially had received human pituitary GH in relatively low doses because of its limited availability. In addition, current GH dosing regimens with regard to frequency of administration have changed, making these data difficult to interpret and apply to the patients who are receiving GH replacement therapy today. Recent studies evaluating the adult height of children who received only recombinant GH therapy with currently recommended dosing regimens suggest that current recombinant GH therapy has a greater impact on final adult height than previously reported.52–55 These studies have reported average final adult heights ranging from 0.5 to 1.7 standard deviations below the population mean. Initiation of therapy at an early chronologic age, prior to the onset of puberty, is associated with a more favorable increase in final height.47,53,54 Therefore, prompt diagnosis of GH deficiency and early initiation of replacement therapy with recombinant GH are crucial factors in optimizing the final adult height of children with GH deficiency.
Recombinant GH has been shown to increase the short-term growth rate in pediatric patients with chronic renal insufficiency, Turner’s syndrome, idiopathic short stature, Prader–Willi syndrome, short stature homeobox gene (SHOX) deficiency, Noonan syndrome, and children born small for gestational age (SGA), and is approved by the FDA for treatment of growth failure associated with these conditions. GH is also FDA approved for treatment of adult GH deficiency, short bowel syndrome in patients receiving specialized nutritional support, and acquired immunodeficiency syndrome wasting syndrome. When used in adult patients, the recommended dosage of recombinant GH is significantly lower than the dosage used in pediatric patients. Adult patients with GH deficiency during childhood must have the diagnosis of GH deficiency confirmed when they are adults. Long-term GH therapy in GHD adults significantly decreases body fat, increases muscle mass, and improves exercise capacity.50 GH therapy in adults has not been definitively shown to improve the cardiac risk profile or bone mineral density, but it does appear to improve psychological well-being.60 The Beers Criteria of the American Geriatrics Society recommends avoiding growth hormone therapy except as replacement after pituitary gland removal because the risks in older adults outweigh any potential benefits.61 Use of GH as an anabolic agent for management of acute catabolism is not recommended.47
The majority of short children in the United States do not have an identifiable medical cause for their condition, but with widespread availability of several recombinant GH formulations, many children have received GH therapy regardless of the underlying etiology of their short stature. The use of recombinant GH therapy in children with non-GHD short stature, also referred to as idiopathic short stature, has been studied by many investigators and was approved by the FDA in 2003.48 However, the use of GH therapy in this patient population remains controversial.62 A meta-analysis of 38 clinical studies evaluating the efficacy of GH treatment in children with idiopathic short stature reported average increases in final adult height of 4 to 5 cm (1.6 to 2 inches) following a mean duration of therapy of 4.7 years.63 This corresponded to an increase above the predicted final adult height of 0.56 to 0.63 standard deviations of the population mean. A recent systematic review of GH treatment in idiopathic short stature noted that the final adult height gain is usually less than that seen in other FDA-approved conditions associated with growth failure, increasing adult height by about 4 cm. The individual response to therapy is highly variable, and further studies are needed to identify responders.64
Ten different recombinant GH products currently are available for use in the United States (Genotropin, Humatrope, Norditropin, Nutropin, Nutropin AQ, Omnitrope, Saizen, Serostim, Tev-Tropin, and Zorbtive). Each of these products contains somatropin. Somatropin is composed of the same amino acid sequence as human pituitary GH. Recombinant GH formulations must be administered by intramuscular or subcutaneous injection. Nutropin AQ, Norditropin, and Omnitrope are the only GH products available as liquid formulations. The remaining products are formulated as lyophilized powders for injection, and patients must be instructed regarding proper administration. A needle-free injection device (Tject) is available for use with Tev-Tropin. This device delivers a thin stream of recombinant GH that penetrates the stratum corneum and deposits into the subcutaneous tissue. This product may be particularly useful for patients who experience significant adverse effects from injections. The potency of GH products is expressed as international units per milligram (international units/mg), with 1 mg containing approximately 2.6 international units of GH. Direct comparisons between the different recombinant GH products have not been published. However, all GH products are generally considered to be equally efficacious. The recommended dose for treatment of GHD short stature in children is 0.3 mg/kg/wk.47,51Recombinant GH can be administered daily or in equal doses six times per week, depending on the specific GH product used.47,51 Dosing regimens with greater frequency of administration have been shown to provide more favorable short-term growth responses.47,51 Recent studies suggest that adjustments in GH replacement can be made based on IGF-1 levels appropriate for age and sex.65GH replacement therapy should be initiated as early as possible after diagnosis of GH insufficiency and continued until a desirable height is reached or growth velocity has decreased to <2.5 cm per year after the pubertal growth spurt. However, the suitable time point for discontinuation of therapy with growth-promoting doses remains controversial. Glucocorticoids may inhibit the growth-promoting effects of recombinant GH, and concomitant administration of androgens, estrogens, thyroid hormones, or anabolic steroids may accelerate epiphyseal closure and compromise final height.
Three large databases, the National Cooperative Growth Study, the Kabi International Growth Study, and the Australian and New Zealand growth database (OZGROW), have been developed to collect postmarketing adverse effect data or reports associated with recombinant GH. Development of these databases was prompted by the unexpected and tragic cases of CJD reported in patients treated with human pituitary GH. These databases are maintained by pharmaceutical companies that manufacture GH products.66,67 Results from the recently released Safety and Appropriateness of Growth Hormone treatments in Europe (SAGhE) study provide additional long-term surveillance data from a noncommercial source.67 Recombinant GH is generally well tolerated in children, and adverse effects are relatively uncommon.66,68 A small number of patients may complain of injection-site pain or arthralgias. Idiopathic intracranial hypertension, also known as pseudotumor cerebri, has been reported in a very small number of children receiving GH therapy. This condition usually develops within the first 8 to 12 of weeks of treatment and presents with symptoms such as headache, blurred vision, diplopia, nausea, and vomiting.66,68 The symptoms of idiopathic intracranial hypertension usually resolve after discontinuation of GH therapy, and long-term complications are rare. Cases of slipped capital femoral epiphysis have been reported in children with GH deficiency who are receiving GH therapy.68 This condition is thought to occur as a result of the increased width of the femoral plate during GH treatment, but it also has been reported in GHD children who are not receiving GH replacement. Patients with this condition typically complain of hip or knee pain. Slipped capital femoral epiphysis can be managed by an orthopedic surgeon, and GH therapy does not need to be withdrawn. Because GH is known to cause decreased insulin sensitivity, hyperglycemia and diabetes mellitus may develop.68 Patients who have specific predisposing risk factors for diabetes mellitus are at greatest risk for this adverse effect.66,68 Glycosylated hemoglobin concentrations should be monitored in all patients receiving GH products.47 GH could theoretically promote the growth of various types of neoplasms and increase tumor recurrence rates in patients with a history of malignancy.47,66,68 For this reason, GH is not administered to patients with an active malignant tumor or a history of recurrent tumor growth. In 1988, a Japanese report indicated that children receiving GH therapy were twice as likely to develop leukemia as children who were not receiving the hormone. A more recent analysis of all collected reports of leukemia associated with GH therapy determined that these children had other leukemia risk factors (Fanconi’s anemia, Bloom’s syndrome, or history of cancer).68 GH therapy in children without these risk factors does not appear to predispose children to develop leukemia.66,68 Concerns were recently raised based on increased mortality rates seen in adult French subjects (SAGhE) who were treated with GH therapy as children.69 The interpretation of these results have been questioned by some because of the large number of children (70%) in the study who had normal stature at baseline and also because of the higher doses of GH used in some patients.70 Another recently published preliminary study from the SAGhE group representing patients from Belgium, The Netherlands, and Sweden did not find similar increases in mortality.71 However, the observational design of these studies makes interpretation of the findings difficult. It should be noted that some authors have stressed the importance of using growth velocity and provocative testing in deciding whom and when to treat, and at what doses.70 Finally, recent postmarketing reports suggest an increased risk of death associated with long-term GH treatment in children with Prader–Willi syndrome who are severely obese or have severe respiratory impairment. GH treatment is contraindicated in patients with Prader–Willi syndrome who have any of these risk factors.
Recombinant Insulin-Like Growth Factor-1
Recombinant IGF-1 (mecasermin [Increlex]) is approved by the FDA for the treatment of children with short stature due to severe primary IGF-1 deficiency (defined as children with height standard deviation score ≤–3.0 plus basal IGF-1 standard deviation score ≤–3.0, plus normal or elevated GH concentration) or GH gene deletion with neutralizing antibodies to GH. A combination of IGF-1 with IGFBP-3 (mecasermin rinfabate) was previously approved by FDA but has since been withdrawn from the market. Recombinant IGF-1 products are not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of antiinflammatory steroids. Recombinant IGF-1 products have been shown to increase growth velocity in children with short stature who have low IGF-1 serum concentrations and resistance to GH.71–74 However, the efficacy of these agents is less than that reported with GH products in patients with GH deficiency.
The recommended dose of mecasermin is 0.04 to 0.12 mg/kg administered by subcutaneous injection twice daily. Because of the insulin-like effects of these products, patients should be monitored very closely for hypoglycemia, and the drug should be initiated at a dose at the lower end of the dosage range and administered with a meal or snack. Additional adverse effects experienced by patients receiving recombinant IGF-1 products include injection-site reactions, tonsillar/adenoidal hypertrophy, lymphoid hypertrophy, coarsening facial features, anaphylaxis, headache, dizziness, and arthralgia.72–74Intracranial hypertension has been reported in a small number of patients.73Additional studies are needed to elucidate the exact role of recombinant IGF-1 products in the management of short stature not caused by GH gene deletion or GH receptor defects.
Personalized Pharmacotherapy
Ongoing genetic studies are attempting to predict GH response in subjects. There is some evidence to suggest that patients with exon-3 deleted GH receptors or a specific polymorphism in the IGFBP-3 promoter gene have an enhanced response to GH therapy. However, recommendations regarding how therapy can be tailored to maximize patient benefit based on these findings are not available at this time. The large number of growth hormone deficiency disorders vary in phenotype and in biochemical and molecular characteristics thereby likely contributing to the variability of response reported in trials with GH or IGF-1. Given this variability, and in the absence of specific and well-validated indicators of response, therapy must be carefully individualized.75
Evaluation of Therapeutic Outcomes
Appropriate monitoring of therapy for GHD and non-GHD short stature includes regular assessments of height, weight, growth velocity, serum IGF-1 concentrations, and bone age every 6 to 12 months. Additional laboratory tests to monitor for potential adverse effects include serum glucose concentration and thyroid function. The dose of GH will periodically need to be increased as weight increases in growing children.
Conclusions
GH deficiency during childhood results in short stature. Replacement with recombinant GH is considered the mainstay of therapy for patients with GHD short stature, but its use for treatment of non-GHD short stature remains controversial, albeit such treatment is FDA approved. Recombinant GH has proven to be safe for use in children and is associated with few adverse effects. Preparations of IGF-1 may provide benefit for patients with non-GHD short stature. GH regimens can be particularly demanding and inconvenient for pediatric patients because they must be administered by subcutaneous injection. Knowledge of the long-term benefits and risks is critical to the development of rational, cost-effective treatments for patients with short stature.
PROLACTIN
Hyperprolactinemia
Prolactin is secreted in a pulsatile fashion by the lactotroph cells of the anterior pituitary, with the highest peak concentrations observed during sleep.4 The secretion of prolactin is regulated primarily by tonic hypothalamic inhibitory effects of dopamine. As described earlier in this chapter and in Table 60-1, many factors can affect prolactin secretion. During pregnancy, prolactin serum concentrations rise substantially above normal. All other conditions characterized by excess prolactin serum concentrations, known as hyperprolactinemia, are considered pathologic. Hyperprolactinemia is a state of persistent serum prolactin elevation. Prolactin concentrations >20 mcg/L (>870 pmol/L) in women, and >25 mcg/L (>1,090 pmol/L) in men, observed on multiple occasions are generally considered indicative of hyperprolactinemia.76 Hyperprolactinemia usually affects women of reproductive age.76–78 The annual incidence of hyperprolactinemia in women between the ages of 24 and 35 years is approximately 24 cases per 1,000 person years.77
Hyperprolactinemia has several etiologies. The most common causes are benign prolactin-secreting pituitary tumors, known as prolactinomas, and various medications. Prolactinomas are classified according to size. Prolactin-secreting microadenomas are <10 mm in diameter and often do not increase in size.4 In contrast, macroadenomas are tumors with a diameter >10 mm that continue to grow and can cause invasion of surrounding tissues.4 In the presence of a prolactinoma, prolactin serum concentrations may remain normal or may be markedly elevated to thousands of micrograms per liter.
Any pharmacologic agent that antagonizes dopamine or increases the release of prolactin can induce hyperprolactinemia (Table 60-4).79 Antipsychotic medications are the most frequently reported agents to cause hyperprolactinemia due to their potent dopamine-receptor blockade. Serotonin is a strong stimulator of prolactin secretion and antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, and tricyclic and tetracyclic agents, are associated with hyperprolactinemia.79 More recently, the 5HT1 receptor agonist eletriptan has been implicated as a potential cause of hyperprolactinemia.80 Metoclopramide and domperidone, an antiemetic available in Europe, are potent dopamine-receptor antagonists reported to induce hyperprolactinemia.79 Hormones such as estrogen and progesterone, commonly prescribed as oral contraceptives, can stimulate lactotroph growth to promote prolactin secretion and have been implicated in drug-induced hyperprolactinemia. Although the exact mechanism of action remains to be determined, the calcium channel-blocking agent verapamil has been associated with cases of hyperprolactinemia.4,79 Methyldopa and reserpine, although not used frequently in clinical practice today, are antihypertensive agents that can stimulate prolactin secretion.79 Prolactin concentrations may increase with administration of GnRH analogs such as leuprolide or goserelin.79 Other medications rarely reported to cause hyperprolactinemia include H2-receptor blocking agents, benzodiazepines, opioids, and protease inhibitors.4,79 Prolactin levels do not typically rise to >150 mcg/L (>6,500 pmol/L) in most cases of drug-induced hyperprolactinemia. Measurement of serum prolactin concentrations prior to the initiation of therapy with medications known to cause prolactin elevation may obviate the need for extensive examination of pituitary function and aid with the appropriate diagnosis of drug-induced hyperprolactinemia.
TABLE 60-4 Drug-Induced Hyperprolactinemia
Less common etiologies include CNS lesions that physically compress the pituitary stalk and interrupt tonic hypothalamic dopamine secretion, resulting in hyperprolactinemia.77 Increased TRH concentrations in hypothyroidism can stimulate prolactin secretion and cause hyperprolactinemia. During conditions of renal or hepatic compromise, the clearance of prolactin is decreased, resulting in elevated prolactin concentrations.77 Despite vigorous diagnostic effort, the cause of hyperprolactinemia cannot always be determined. This is known as idiopathic hyperprolactinemia and most likely is a result of the presence of very small tumors that are not detected by standard imaging techniques.76 It should be noted that many physiologic factors, such as stress (including the stress of phlebotomy), sleep, exercise, coitus, and eating, also can induce transiently elevated prolactin levels.4,76 This emphasizes the importance of obtaining multiple prolactin measurements to confirm the diagnosis. Ideally, after an IV line is placed in the patient’s arm, the patient should rest in a supine position or in a chair for 2 hours before prolactin samples are collected.
Elevated prolactin serum concentrations inhibit gonadotropin secretion and sex-steroid synthesis.76 Because prolactin concentrations >60 mcg/L (>2,600 pmol/L) are associated with anovulation, women with hyperprolactinemia typically present with menstrual irregularities such as oligomenorrhea or amenorrhea and infertility.76,77 In addition, approximately 40% to 80% of women with hyperprolactinemia will have galactorrhea.76,77 The clinical presentation of patients with hyperprolactinemia is summarized in Table 60-5.4,76,77
TABLE 60-5 Clinical Presentation of Hyperprolactinemia
The diagnosis of hyperprolactinemia, as defined by a prolactin serum concentration >25 mcg/L (>1,090 pmol/L), is relatively simple.77 However, identifying the underlying cause of this abnormality may be more challenging. Patients with modest prolactin elevations should have multiple prolactin serum determinations to minimize the potential for detecting only transient increases in prolactin. A careful medication history is essential, and the presence of hypothyroidism, renal failure, or hepatic dysfunction should be evaluated. If the cause of hyperprolactinemia remains ambiguous, a computed tomography scan or magnetic resonance imaging study should be performed to determine the presence of a pituitary tumor.76,77 If an underlying cause of elevated prolactin serum concentration is not determined, the hyperprolactinemia is considered to be idiopathic.
Clinical Controversy…
For patients with antipsychotic-induced hyperprolactinemia in whom it is not feasible to withdraw the offending agent, treatment with dopamine agonists is controversial due to the potential for exacerbation of the underlying psychosis.
TREATMENT
Hyperprolactinemia
The treatment of hyperprolactinemia depends on the underlying cause of the abnormality. In cases of drug-induced hyperprolactinemia, discontinuation of the offending medication and initiation of an appropriate therapeutic alternative usually normalize serum prolactin concentrations.79 In cases for which an appropriate therapeutic alternative does not exist, medical therapy with dopamine agonists may be carefully considered.77 Sex-steroid replacement also should be considered.77 Treatment options for the management of prolactinomas include clinical observation, medical therapy with dopamine agonists, radiation therapy, and transsphenoidal surgical removal of the tumor.4,76–78Because prolactin-secreting microadenomas are very small and typically do not increase in size, treatment of these tumors is primarily directed toward alleviating symptoms.76–78 The goal of therapy is to normalize prolactin serum concentrations and reestablish gonadotropin secretion to restore fertility and reduce the risk of osteoporosis. In patients with asymptomatic elevations in serum prolactin, observation and close follow-up are appropriate.76–78 For women with amenorrhea who do not wish to become pregnant, dopamine agonist therapy may not be necessary. In these patients, sex-steroid replacement and close follow-up may be sufficient.76 Treatment goals are more aggressive in patients with prolactin-secreting macroadenomas because these tumors are larger and can cause invasion of local tissues with significant visual defects.78 Therefore, in addition to normalizing prolactin concentrations, tumor shrinkage and correction of visual defects are primary goals of treatment.
Medical therapy with dopamine agonists usually is more effective than transsphenoidal surgery for both types of pituitary prolactinomas.4,76–78 Postsurgical cure rates differ depending on tumor type and expertise of the neurosurgeon. Long-term cure rates are reported to be approximately 60% for microprolactinomas and only 25% for macroprolactinomas.4 Transsphenoidal surgery for removal of prolactinomas usually is reserved for patients who are refractory to or cannot tolerate therapy with dopamine agonists and for patients with very large tumors that cause severe compression of adjacent tissues.4,76–78 Radiation therapy may require several years for effective tumor shrinkage and reduction in serum prolactin concentrations and usually is used only in conjunction with surgery.4
Pharmacologic Therapy
Medical therapy with dopamine agonists has proven to be very effective in normalizing prolactin serum concentrations, restoring gonadal function, and reducing tumor size.4,77 Cabergoline, a long-acting dopamine agonist that offers the advantage of less-frequent dosing, is the agent of choice for the medical management of prolactinomas because of its superior efficacy in comparison to bromocriptine.77
Bromocriptine
Bromocriptine was the first D2-receptor agonist to be used in the treatment of hyperprolactinemia and had been the mainstay of therapy for over 20 years. It inhibits the release of prolactin by directly stimulating postsynaptic dopamine receptors in the hypothalamus. Hypothalamic release of dopamine (prolactin-inhibitory hormone) inhibits the release of prolactin. Decreases in serum prolactin concentrations occur within 2 hours of oral administration, with maximal suppression occurring after 8 hours and suppressive effects persisting for up to 24 hours. Medical therapy with bromocriptine normalizes prolactin serum concentrations, restores gonadotropin production, and shrinks tumor size in approximately 90% of patients with microprolactinomas and 70% of patients with macroprolactinomas.78
For the management of hyperprolactinemia, bromocriptine therapy typically is initiated at a dose of 1.25 to 2.5 mg once daily at bedtime to minimize adverse effects.76 The dose can be gradually increased by 1.25-mg increments every week to obtain desirable serum prolactin concentrations. Usual therapeutic doses of bromocriptine range from 2.5 to 15 mg/day, although some patients may require doses as high as 40 mg/day.77 Bromocriptine usually is administered in two or three divided doses, but once-daily dosing has also been shown to be effective.78
The most common adverse effects associated with bromocriptine therapy include CNS symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue. GI effects such as nausea, abdominal pain, and diarrhea also are common. Bromocriptine should be administered with food to decrease the incidence of adverse GI effects. Although most of these adverse effects diminish with continued treatment, approximately 12% of patients will not tolerate the adverse effects associated with bromocriptine therapy.78 Vaginal preparations of bromocriptine have been studied in an effort to decrease the incidence of adverse effects associated with oral dosage forms.4,77,81
Because most patients with hyperprolactinemia are women with a principal complaint of infertility, the safety of bromocriptine in pregnancy must be considered. Greater than 6,000 pregnancies have been reported in women who received bromocriptine throughout gestation, and an increased risk for spontaneous abortion or congenital anomalies has not been detected.77 Although bromocriptine does not appear to be teratogenic, most clinicians discontinue therapy as soon as pregnancy is detected because the effects of in utero exposure to bromocriptine on gonadal function and fertility of the offspring remain unknown.4,76–78 In patients with macroprolactinomas undergoing rapid tumor expansion, bromocriptine therapy may need to be continued throughout pregnancy.
Cabergoline
Cabergoline is a long-acting dopamine agonist with high selectivity and affinity for dopamine D2-receptors. This agent is approved for treatment of hyperprolactinemia and has been shown to effectively reduce serum prolactin concentrations and tumor size in patients with both microprolactinomas and macroprolactinomas.77 A recent systematic review and meta-analysis of four clinical trials comparing the efficacy of cabergoline and bromocriptine reported that cabergoline was significantly more effective in normalizing serum prolactin concentrations.82 Cabergoline has also proved effective in patients who are intolerant of or resistant to bromocriptine, and the data suggest that cabergoline is as effective in men as in women with microprolactinomas and macroprolactinomas.77,83
Cabergoline is commercially available as 0.5-mg oral tablets. The initial dose of cabergoline for treatment of hyperprolactinemia is 0.25 to 0.5 mg once weekly or in divided doses twice weekly. This dose may be increased by 0.5-mg increments at 4-week intervals based on serum prolactin concentrations.84 The usual dose is 1 to 2 mg weekly; doses >3 mg per week are infrequently required. However, doses as high as 12 mg weekly have been used safely in patients with treatment-resistant prolactinomas.85 Following oral administration, peak serum concentrations are obtained within 2 hours, and food does not affect absorption. The elimination of cabergoline from the pituitary appears to be very slow; this rate may explain the long duration of action. Cabergoline is extensively metabolized in the liver by hydrolysis, and the dose should be reduced in patients with severe hepatic failure. This drug is eliminated primarily in the feces, and the elimination half-life ranges from 79 to 155 hours in hyperprolactinemic patients.
The most common adverse effects reported with use of cabergoline are nausea, vomiting, headache, and dizziness.78,84 These effects are similar to the adverse effects reported with bromocriptine. However, in a large comparative study evaluating bromocriptine and cabergoline, fewer patients receiving cabergoline reported adverse effects than did patients receiving bromocriptine, and only 3% of the patients in the cabergoline group withdrew from the study because of adverse effects versus 12% of patients taking bromocriptine.86 Other adverse events associated with use of cabergoline include constipation, fatigue, anxiety, depression, and nasal congestion.77,84 As with other dopamine agonists, adverse events usually occur early in therapy and subside with continued treatment. However, in one study 15% to 20% of patients receiving cabergoline experienced a recurrence of early symptoms or an onset of new symptoms after several weeks of treatment.86 Mild-to-moderate decreases in blood pressure have been observed in up to 50% of patients taking cabergoline; however, the incidence of symptomatic orthostatic hypotension has not been significant.84,86 Transient increases in serum alkaline phosphatase, bilirubin, and aminotransferases have been reported in small numbers of patients receiving cabergoline.86 Pleuropulmonary disease78 and newly diagnosed cardiac valve regurgitation87 have been reported with cabergoline use at the larger doses used in the treatment of Parkinson’s disease. Although symptomatic cardiac valve abnormalities have not been observed with cabergoline when administered in doses used for the treatment of prolactinomas, some clinicians have recommended routine echocardiography for patients receiving long-term cabergoline treatment for prolactinomas.88,89
Use of cabergoline in pregnancy has not been extensively studied. However, several case reports of women who received cabergoline therapy during the first and second trimesters of pregnancy have not documented an increased risk of spontaneous abortion, congenital abnormalities, or tubal pregnancy.90 However, prospective data in large numbers of pregnancies are lacking. Because of the long half-life and limited data on cabergoline use in pregnancy, current guidelines recommend that women receiving cabergoline therapy who plan to become pregnant should discontinue the medication as soon as pregnancy is detected.77
Other dopamine agonists that have been used in the treatment of hyperprolactinemia but are not commercially available in the United States include lisuride, terguride, metergoline, dihydroergocristine, and quinagolide.78Quinagolide, a D2-receptor agonist used frequently in Europe, is dosed once daily. Quinagolide has been shown to be as effective as bromocriptine for the management of hyperprolactinemia and may be effective in the treatment of patients who are resistant to or intolerant of bromocriptine.78
Personalized Pharmacotherapy
Genetic predisposition to the development of hyperprolactinemia has been reported involving the D2 receptor and hormone-related genes.91,92 However, recommendations regarding how therapy can be individualized to maximize patient benefit are not available.
Evaluation of Therapeutic Outcomes
Prolactin serum concentrations should be monitored every 3 to 4 weeks after the initiation of any dopamine-agonist therapy to assess efficacy and appropriately titrate medication dosage.76 In addition, symptoms such as headache, visual disturbances, menstrual cycles in women, and sexual function in men should be evaluated to assess clinical response to therapy. Once prolactin concentrations have normalized and clinical symptoms of hyperprolactinemia have resolved with dopamine-agonist therapy, prolactin serum concentrations should be monitored every 6 to 12 months. In patients receiving long-term treatment, the dose of the dopamine agonist can be gradually reduced or discontinued in some patients. For patients who have received medical therapy with dopamine agonists for at least 2 years, therapy may be tapered or discontinued if normal serum prolactin concentrations are achieved in the absence of visible tumor.77 Follow-up of such patients should include prolactin serum concentration measurements every 3 months for the first year (continued annually thereafter), with assessment of MRI findings if prolactin concentrations are elevated.
Conclusions
Hyperprolactinemia is a common disorder that can have a significant impact on fertility. Hyperprolactinemia is most commonly caused by the presence of prolactin-secreting pituitary tumors and various medications that antagonize dopamine or increase the secretion of prolactin. Available treatment options for this disorder include medical therapy with dopamine agonists, radiation therapy, and transsphenoidal surgery. In most cases, medical therapy with dopamine agonists is considered the most effective treatment. Cabergoline is the mainstay of medical therapy because it appears to be better tolerated and more effective.
PANHYPOPITUITARISM
Panhypopituitarism is a condition of complete or partial loss of anterior and posterior pituitary function resulting in a complex disorder characterized by multiple pituitary hormone deficiencies. Patients with panhypopituitarism may have ACTH deficiency, gonadotropin deficiency, GH deficiency, hypothyroidism, and hyperprolactinemia. Panhypopituitarism can be classified as either primary or secondary depending on the etiology. Primary panhypopituitarism involves an abnormality within the secretory cells of the pituitary, whereas secondary panhypopituitarism is caused by a lack of proper external stimulation needed for normal release of pituitary hormones. Some of the most common causes of panhypopituitarism include primary pituitary tumors, ischemic necrosis of the pituitary, surgical trauma, irradiation, and various types of CNS infections. Pharmacologic treatment of panhypopituitarism is essential and consists of replacement of specific pituitary hormones after careful assessment of individual deficiencies. Replacement most often consists of glucocorticoids, thyroid hormone preparations, and sex steroids. Administration of recombinant GH also may be necessary. Patients with panhypopituitarism will need lifelong replacement therapy and constant monitoring of multiple homeostatic functions.
ACKNOWLEDGMENT
This research was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health.
ABBREVIATIONS
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