Judy T. Chen, Devra K. Dang, Frank Pucino Jr., and Karim Anton Calis
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. List the mediators and primary effects of pituitary hormones.
2. Identify clinical features of patients with acromegaly.
3. Discuss the role of surgery and radiation therapy for patients with acromegaly.
4. Select appropriate pharmacotherapy for patients with acromegaly based on patient-specific factors.
5. Identify clinical features of children and adults with growth hormone (GH) deficiency and select appropriate pharmacotherapy for these patients.
6. Recommend monitoring parameters necessary to assess therapeutic outcomes and adverse effects in patients receiving GH therapy.
7. List common etiologies of hyperprolactinemia.
8. Identify clinical features of patients with hyperprolactinemia.
9. Select appropriate pharmacologic and nonpharmacologic treatments for patients with hyperprolactinemia based on patient-specific factors.
KEY CONCEPTS
Surgical resection of the pituitary tumor through transsphenoidal pituitary microsurgery is the treatment of choice for most patients with growth hormone (GH)-producing pituitary adenomas.
Somatostatin analogs are the mainstay of pharmacotherapy for the treatment of acromegaly when surgery is contraindicated or has failed.
Pegvisomant is indicated for patients who do not tolerate or fail other treatments, or for those with extremely elevated insulin-like growth factor (IGF) I levels.
Dopamine agonists may be appropriate for patients with mildly elevated IGF-I levels who have GH and prolactin cosecreting tumors.
Prolonged exposure to elevated GH and IGF-I levels can lead to serious complications in patients with acromegaly. Aggressively manage comorbid conditions such as hypertension, diabetes, dysrhythmias, coronary artery disease, and heart failure to prevent vascular and/or neuropathic complications.
Recombinant GH therapy is the main pharmacologic treatment for GH deficiency in both children and adults.
Although comparative trials have not been conducted, recombinant GH products appear to have similar efficacy for treating GH deficiency.
Dopamine agonists are the first-line treatment of choice for all patients with hyperprolactinemia; transsphenoidal surgery and radiation therapy are reserved for patients who are resistant to or severely intolerant of pharmacologic therapy.
Women who become pregnant while on a dopamine agonist should discontinue treatment immediately to minimize fetal exposure. Because cabergoline has a long half-life, women who plan to become pregnant should discontinue the drug at least 1 month before planned conception.
PHYSIOLOGY OF THE PITUITARY GLAND
The pituitary gland, located at the base of the brain in proximity to the nasal cavity, is a small endocrine gland about the size of a pea weighing approximately 600 mg. The pituitary gland is referred to as the “master gland” because it is responsible for the regulation of many other endocrine glands and body systems. Growth, development, metabolism, reproduction, and stress homeostasis are among the functions influenced by the pituitary. Functionally, the gland consists of two distinct sections: the anterior pituitary lobe (adenohypophysis) and the posterior pituitary lobe (neurohypophysis). The pituitary receives neural and hormonal input from the inferior hypothalamus via blood vessels and neurons contained in the pituitary stalk (infundibulum).
FIGURE 46–1. Hypothalamic–pituitary–target-organ axis. The hypothalamic hormones regulate the biosynthesis and release of eight pituitary hormones. Stimulation of each of these pituitary hormones produces and releases trophic hormones from their associated target organs to exert their principal effects. These trophic hormones regulate the activity of endocrine glands. Subsequently, increased serum concentration of the trophic hormones released from the target organs can inhibit both the hypothalamus and the anterior pituitary gland to maintain homeostasis (negative feedback). Inhibin is produced by the testes in the male and ovaries in the female during pregnancy. Inhibin directly inhibits pituitary production of follicle-stimulating hormone (FSH) through a negative feedback mechanism. Melanocyte-stimulating hormone (MSH) produced by the anterior pituitary is not illustrated in the figure [(−), inhibit; (+), stimulate; ACTH, adrenocorticotropic hormone (corticotropin); ADH, antidiuretic hormone (vasopressin); CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GABA, γ-aminobutyric acid; GH, growth hormone (somatotropin); GHIH, growth hormone–inhibiting hormone (somatostatin); GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone; PRH, prolactin-releasing hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone (thyrotropin).]
The posterior pituitary is innervated by nervous stimulation from the hypothalamus, resulting in the release of specific hormones to exert direct tissue effects. The hypothalamus synthesizes two hormones, oxytocin and vasopressin. These hormones are stored in and released from the posterior pituitary lobe. Oxytocin exerts two actions, it: (a) promotes uterine contractions during labor and (b) contracts the smooth muscles in the breast to stimulate the release of milk from the mammary gland during lactation. Vasopressin is an antidiuretic hormone essential for proper fluid and electrolyte balance in the body. Specifically, vasopressin increases the permeability of the distal convoluted tubules and collecting ducts of the nephrons to water. This causes the kidney to excrete less water in the urine. Consequently, the urine becomes more concentrated as water is conserved.
In contrast to the posterior pituitary lobe, the anterior pituitary lobe is under the control of several releasing and inhibiting hormones secreted from the hypothalamus via a portal vein system. The anterior pituitary, in turn, synthesizes and secretes six major hormones. Figure 46–1 summarizes the physiologic mediators and effects of each of these hormones.
Hormonal Feedback Regulatory Systems
The hypothalamus is responsible for the synthesis and release of hormones that regulate the pituitary gland. Stimulation or inhibition of the pituitary hormones elicits a specific cascade of responses in peripheral target glands. In response, these glands secrete hormones that exert a negative feedback on other hormones in the hypothalamic–pituitary axis (Fig. 46–1). This negative feedback serves to maintain body system homeostasis. High circulating hormone levels inhibit the release of hypothalamic and anterior pituitary hormones.
Damage and destruction of the pituitary gland may result in secondary hypothyroidism, hypogonadism, adrenal insufficiency, growth hormone (GH) deficiency, hypopro-lactinemia, or insufficiency or absence of all anterior pituitary hormones (i.e., panhypopituitarism). A tumor (adenoma) located in the pituitary gland may result in excess secretion of a hormone or may physically compress the gland and suppress adequate hormone release. The type, location, and size of a pituitary tumor often determine a patient’s clinical presentation. This chapter discusses the pathophysiology and role of pharmacotherapy in the treatment of acromegaly, GH deficiency, and hyperprolactinemia. The following hormones are discussed elsewhere in this textbook: adrenocorticotropic hormone (ACTH or corticotropin), thyroid-stimulating hormone (TSH or thyrotropin), luteinizing hormone (LH), follicle-stimulating hormone (FSH), vasopressin (antidiuretic hormone), and oxytocin.
GH (SOMATOTROPIN)
Somatotropin or GH is the most abundant hormone produced by the anterior pituitary lobe. The GH-secreting somatotropes account for 50% of hormone–secreting cells in the anterior pituitary. GH is regulated primarily by the hypothalamic-pituitary axis. The hypothalamus releases growth hormone–releasing hormone (GHRH) to stimulate GH synthesis and secretion, whereas somatostatin inhibits it.1 Upon stimulation by GHRH, somatotropes release GH into the circulation, thereby stimulating the liver and other peripheral target tissues to produce insulin-like growth factors (IGFs). These IGFs, also known as somatomedins, are the peripheral GH targets. There are two types of IGFs: IGF-I and IGF-II. IGF-II is responsible primarily for regulating fetal growth, whereas IGF-I is the hormone responsible for growth of bone and other tissues. High levels of IGF-I inhibit GH secretion through somatostatin, thereby inhibiting GHRH secretion.1 The hypothalamus also may stimulate the release of somatostatin to inhibit GH secretion. Effects of IGF-I in peripheral tissues are both GH-dependent and GH-independent.2 GH is an anabolic hormone with direct “anti-insulin” metabolic effects. By stimulating protein synthesis and shifting the body’s energy source from carbohydrates to fats, GH promotes a diabetic state (Table 46–1).2 GH controls somatic growth and has a critical role in the development of normal skeletal muscle, myocardial muscle, and bone.
In healthy individuals, GH is secreted in a pulsatile pattern throughout a 24-hour period, with several short bursts occurring mostly during the night. The most intense period of GH secretion occurs within the first 1 to 2 hours of slow-wave sleep (stage 3 or 4 deep sleep).1 In between these bursts, basal concentration of GH falls to very low or undetectable levels because of its short half-life in the blood (approximately 19 minutes). The amount of GH secretion fluctuates throughout a person’s lifetime. Secretion of GH is lowest during infancy, increases during childhood, peaks during adolescence, and then declines gradually during the middle years.1 These changes are parallel to an age-related decline in lean muscle mass.
Table 46–1 Effects of Growth Hormone
GH Excess
Epidemiology and Etiology
Acromegaly affects both genders equally, and the average age of presentation is 44 years. Approximately 50 to 70 people per 1 million population are affected, with an estimated annual incidence of 3 to 4 cases per 1 million people.3–5 In more than 95% of the cases, overproduction of GH is due to a benign pituitary tumor (adenoma), whereas malignant tumors occur in less than 1%.3 Most pituitary adenomas occur spontaneously as a result of a genetic mutation acquired during life. Depending on the size of the tumor, pituitary adenomas are classified as: (a) microadenomas if they are 10 mm or less in diameter; or (b) macroadenomas if they are greater than 10 mm. Rarely, nonpituitary tumors cause acromegaly. These tumors can produce GH, but more commonly they secrete GHRH and result in excessive GH and IGF-I production.
Pathophysiology
Acromegaly is a rare, insidious disorder that manifests gradually over time. It is caused by an adenoma of the pituitary that overproduces GH and stimulates excessive production of IGF-I during adulthood. This typically occurs after fusion of the epiphyses (growth plates) of the long bones.3 The facial features of an acromegalic patient are depicted in Figure 46–2. Gigantism refers to GH excess that occurs during childhood before epiphyseal closure and results in excessive linear growth.
Diagnosis of acromegaly is based on both clinical and biochemical findings. Because secretion of GH fluctuates throughout the day, a single random measurement is never reliable for diagnosing GH excess.1However, GH-mediated IGF-I production results in relatively stable serum IGF-I concentrations during the day, which correlate positively with 24-hour mean GH levels.1 This makes elevated IGF-I levels an ideal screening test for acromegaly and a reliable monitoring biochemical marker to assess disease activity and response to therapy.6,7 Because IGF-I levels may fluctuate with age and gender, it is important to compare IGF-I levels with age- and sex-matched population values.6,7 Other conditions such as nutritional status, liver dysfunction, insulin levels, and illness also can affect IGF-I levels. The measurement of serum GH secreted by the pituitary in response to an oral glucose tolerance test (OGTT) is the primary biochemical test for diagnosing acromegaly. GH is suppressed after administration of a 75 g oral glucose challenge because postprandial hyperglycemia inhibits secretion of GH for at least 1 hour. If the GH level does not decline to less than 1 ng/mL (1 mcg/L) during the test, the patient is diagnosed with acromegaly.3 In addition to clinical presentation, elevated IGF-I serum concentration helps to confirm the diagnosis.
Acromegaly Treatment Goals
Patients with untreated acromegaly experience a twofold increase in mortality rate primarily due to cardiovascular and pulmonary diseases.10 Normalization of GH and IGF-I levels reverses the mortality risk and alleviates significant comorbid complications, especially cardiovascular, pulmonary, metabolic, and respiratory abnormalities.11 Reduction of IGF-I levels alone does not appear to be a reliable predictor of long-term outcome.6,12 The goals of therapy are as follows3,13–15:
• Normalize biochemical markers.
• Reduce GH to less than 1 ng/mL (1 mcg/L) after OGTT. When using the older GH assay, suppression of GH levels to less than 1 ng/mL (1 mcg/L) after OGTT is the biochemical target. Lower cut off levels have been suggested using the more sensitive GH assays.13–15
• Normalize IGF-I levels to age- and sex-matched control values.
• Ablate or reduce tumor size to relieve tumor mass effect.
• Prevent tumor recurrence and control tumor size.
• Preserve normal pituitary function.
• Improve clinical signs and symptoms.
• Alleviate significant morbidities.
• Reduce mortality rates to that of the general population.
General Approaches to Treatment
The American Association of Clinical Endocrinologists published medical guidelines for the diagnosis and treatment of acromegaly (Fig. 46–3). According to these guidelines, surgical resection of the pituitary tumor through transsphenoidal pituitary microsurgery is the treatment of choice for most patients with GH-producing pituitary adenomas.3 When performed by experienced surgeons, approximately 70% to 80% of patients with microadenomas and less than 50% of patients with macroadenomas achieve biochemical control.10 Complete resection of a macroadenoma may be difficult if the tumor has already invaded the surrounding nerves and tissues. In such cases, debulking of the tumor along with adjunctive radiation and/or pharmacotherapy may improve treatment outcome. Infrequent surgical complications include meningitis, serious visual impairment, cerebrospinal fluid leakage, diabetes insipidus, and permanent hypopituitarism.3 Relative contraindications to surgery include patient frailty, acromegaly-associated comorbidities, and medically unstable conditions such as airway difficulties, severe hypertension, or uncontrolled diabetes.
FIGURE 46–2. Before and after photographs of an acromegalic patient. Compare the photographs of an acromegalic woman (A) before the onset of acromegaly and (B) after approximately 20 years, when the diagnosis was well established. Notice the coarsening of facial features, with enlarged nose, lips, and forehead.
Clinical Presentation and Diagnosis of Acromegaly
General
The patient will experience slow development of soft-tissue overgrowth affecting many body systems. Signs and symptoms may progress gradually over 7 to 10 years.
Symptoms
• Headache and compromised visual function (loss of peripheral vision and blurred vision) caused by the actual tumor mass and its close proximity to the optic structures.
• Loss of other hormonal functions (i.e., LH, FSH, TSH, and ACTH) caused by massive tumor size compressing the anterior pituitary lobe.
• Absence of regular menstrual periods (amenorrhea), impotence, and decreased libido caused by disruption of the gonadotropin secretion.
• Excessive sweating, joint pain, nerve pain, and abnormal neurologic sensations (paresthesias) related to elevated GH and IGF-I levels.
Signs
• Coarsening of facial features
• Increased hand volume
• Increased ring and shoe size
• Increased spacing between teeth
• Increased acne/oily skin
• Enlarged tongue
• Deepening of voice
• Thick, irregular, patchy skin discoloration
• Enlarged nose, lips, and forehead (frontal bossing)
• Abnormal protrusion of the mandible (prognathia)
• Inappropriate secretion of breast milk (galactorrhea)
• Abnormal enlargement of various organs (organomegaly) such as liver, spleen, and heart
• Carpal tunnel syndrome caused by nerve compression from the swollen tissue
Laboratory Tests
• GH level greater than 1 ng/mL (1 mcg/L) following an OGTT and elevated IGF-I level compared with age- and sex-matched control values
• Glucose intolerance may be present in up to 50% of patients
Additional Clinical Sequelae
• Cardiovascular diseases: hypertension, coronary heart disease, cardiomyopathy, left ventricular hypertrophy, and arrhythmia
• Osteoarthritis and joint damage develop in up to 90% of patients
• Respiratory disorders and sleep apnea occur in up to 60% of patients
• Type 2 diabetes mellitus develops in 25% of patients
• Increased risk for the development of esophageal, colon, and stomach cancer
Other Diagnostic Tests
• Perform MRI examination and CT of the pituitary to locate the tumor and validate the diagnosis.
• Without obvious pituitary tumor but proven acromegaly, measurement of GHRH may be helpful to detect ectopic tumors.
Adapted, from Sheehan AH, Yanovski JA, Calis KA. Pituitary Gland Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy. A Pathophysiologic Approach. 7th ed. New York: McGraw Hill, 2008:1284.
From Refs. 4, 8, 9.
Pharmacologic Therapy
Pharmacologic therapy is often necessary for patients in whom surgery is not an option. Somatostatin analogs, GH receptor antagonists, and dopamine agonists are the primary pharmacologic therapies used for the management of acromegaly (Table 46–2).3 Pharmacologic therapy avoids hypopituitarism and other surgical risks.
Somatostatin Analog (GH-Inhibiting Hormone)
Somatostatin analogs are the mainstay of pharmacotherapy for the treatment of acromegaly when surgery is contraindicated or has failed. These agents mimic endogenous somatostatins and bind to the somatostatin receptors in the pituitary to cause potent inhibition of GH, insulin, and glucagon secretion. Long-term treatment can sustain hormone suppression, alleviate soft-tissue manifestations, and reduce tumor size. Use of the first-generation somatostatin analog, octreotide, is limited by its extremely short duration of action which necessitates frequent injections of at least three times per day. The long-acting preparations of octreotide and lanreotide are considered the cornerstone of therapy due to improved patient adherence and acceptability. Typically, at least a 2-week trial of short-acting octreotide is recommended to determine efficacy and tolerance before switching to a long-acting preparation. The long-acting formulations can be administered every 14 to 28 days. Their efficacy and safety have been demonstrated in long-term studies (up to 9 years with octreotide and 4 years with lanreotide).16–18 Long-acting octreotide effectively suppresses GH levels and achieves normal IGF-I levels in 67% and 57% of patients, while lanreotide slow-release formulation achieved lower response rates of 48% and 47%, respectively.19 However, the response rate of long-acting octreotide may be overestimated due to differences in subject selection.19 Recent limited data suggested treatment with lanreotide autogel is comparable to lanreotide slow-release and as effective as long-acting octreotide.18 Since somatostatin analogs can achieve substantial relief of clinical symptoms with significant reduction in tumor size,19,20 it is important to monitor patients for tumor recurrence if treatment is discontinued. Due to lack of sufficient data, routine use of presurgical somatostatin analogs is currently not recommended unless a delay in surgery is anticipated.18
FIGURE 46–3. Management of growth hormone–producing adenomas (GH, growth hormone; IGF-I, insulin-like growth factor I.) (Adapted from Ref. 3.)
Somatostatin analogs are generally well tolerated. Common adverse effects include transient GI disturbances such as diarrhea, abdominal pain, flatulence, constipation, and nausea.18 These adverse GI effects usually subside within the first 3 months of therapy.5 Somatostatin analogs inhibit gallbladder contractility and decrease bile secretion; therefore, their major adverse effect is development of biliary sludge and asymptomatic gallstones(cholelithiasis). Biliary sludge is a predisposing factor for the high incidence of cholelithiasis observed in up to 20% of patients.5 Development of gallstones typically occurs in patients treated for 12 months or longer and is unrelated to age, gender, or dose. Somatostatin analog-induced gallstones should be managed according to standard guidelines.5 Additionally, somatostatin analogs may alter the balance of counterregulatory hormones (i.e., glucagon, insulin, and GH), resulting in either hypoglycemia or hyperglycemia.18 Octreotide also may suppress pituitary release of TSH, leading to decreased thyroid hormone secretion and subsequent hypothyroidism in 12% of treated patients. Close monitoring of thyroid function and glucose metabolism is recommended. Sinus bradycardia, conduction abnormalities, and arrhythmias have been reported with octreotide and lanreotide. Due to the potential adverse effects of the somatostatin analogs, concomitant use with insulin, oral hypoglycemic agents, β-blockers, or calcium channel blockers may require careful dosage adjustment. Somatostatin analogs also may alter the bioavailability and elimination of cyclosporine, and monitoring of cyclosporine serum concentration is necessary.
Table 46–2 Comparison of Various Drugs for Treatment of Acromegaly
GH-Receptor Antagonist
GH-receptor antagonist represents a novel approach to the treatment of acromegaly. Pegvisomant is the only genetically engineered GH-receptor antagonist that blocks the action of GH. The effects of pegvisomant work independently of tumor characteristics, somatostatin, and dopamine receptors.21 Up to 97% of acromegalic patients treated with pegvisomant (10–20 mg/day) achieved normal age-related IGF-I levels and experienced significant improvement in clinical symptoms of GH excess by 1 year of therapy.22,23 In patients previously resistant to somatostatin analog therapy, normal IGF-I concentrations were achieved in 75% of patients treated with pegvisomant24 and in 69% to 100% of patients treated with pegvisomant and somatostatin analog therapy.25–27 Pegvisomant therapy may have favorable effects on glucose tolerance (the body’s ability to metabolize glucose) and insulin sensitivity (capacity of cells to respond to insulin).24 However, use of pegvisomant is associated with significant dose-dependent increases in GH despite the declining IGF-I levels.22,23 The dose-dependent increase in GH is troubling because it has been suggested that persistent elevation of GH levels may be indicative of tumor growth. Thus, careful monitoring with periodic imaging scans is indicated, especially when administering pegvisomant to patients at risk for visual damage from large tumors that may impinge on the optic chiasm. Pegvisomant is indicated for patients who do not tolerate or fail other treatment options, or for those with extremely elevated IGF-I levels (greater than 900 ng/mL or 900 mcg/L).3 Long-term efficacy and safety profiles of pegvisomant in acromegaly remain to be established. Available data suggest that pegvisomant appears well-tolerated with minimal adverse effects such as self-limiting injection-site reactions, nausea, diarrhea, infection, and flu-like symptoms. Approximately 17% of patients who receive pegvisomant develop non-neutralizing anti-GH antibodies. Although the long-term consequences are unknown, the presence of antibodies does not appear to affect the efficacy of pegvisomant. Cases of hepatotoxicity have been reported in clinical trials,22,23 with a higher risk observed in diabetics receiving combined pegvisomant and somatostatin analogs.27 Therefore, obtain baseline levels of transaminases, total bilirubin, and alkaline phosphatase prior to initiating therapy and periodically thereafter. Caution should be used when administering pegvisomant to patients with elevated liver function tests, and therapy should be discontinued in the presence of clinical signs and symptoms of hepatic injury.
Dopamine Agonists
Dopamine is one of the neuro-transmitters that can increase GH secretion in healthy adults. However, dopamine agonists administered to patients with acromegaly exert the opposite effect and suppress GH release from the tumor. The first dopamine agonist for acromegaly, bromocriptine, achieved normal IGF-I levels in fewer than 10% of patients and was associated with significant adverse effects, including nausea, dizziness, and headaches.10 The large doses of bromocriptine required to achieve the desired response often are associated with dose-limiting toxicity, such as GI discomfort and orthostatic hypotension. Cabergoline, the selective long-acting agonist with improved tolerability, effectively can normalize IGF-I levels in 35% of patients and reduce GH levels in 44% of patients.28 Acromegalic patients with coexisting hyperprolactinemia also had a more favorable response to cabergoline, with 50% of patients achieving normal IGF-I levels, 56% GH suppression, and 65% tumor shrinkage.28Although orally administered dopamine agonists are the least expensive medical therapy for managing acromegaly, the major disadvantage is their relative lack of efficacy compared with existing therapeutic options. Dopamine agonists may be appropriate for patients with mildly elevated IGF-I levels who have GH and prolactin cosecreting tumors.3
Radiation Therapy
Radiation therapy is an important adjunctive therapy in patients with residual GH excess following surgery or pharmacologic therapy. Treatment involves the use of radiation to destroy rapidly growing tumor cells and often results in a reduction in tumor size. A major complication resulting from radiation therapy is hypopituitarism, requiring lifelong hormone replacement.3 There is also the potential for optic nerve damage if the pituitary tumor is near the optic tracts. Radiation therapy may take 10 to 20 years before its full effects become evident.10 Owing to delay in onset of radiation effectiveness, pharmacologic therapy often is indicated as bridge therapy.3 Men and women who desire to have children should be warned that pituitary irradiation therapy may impair fertility.3
Outcome Evaluation
• Following a baseline evaluation, monitor patients regularly for symptom relief. See Acromegaly: Patient Care and Monitoring text Box
• Lifelong biochemical assessment is critical for determining therapeutic outcomes. Although some patients may experience a rapid decline in GH levels following transsphenoidal microsurgery, stabilization of IGF-I levels usually occurs 3 months following surgery but rarely may be delayed for up to 12 months. Measure GH and IGF-I levels 3 months postoperatively to assess treatment response.6
• Because up to 10% of pituitary tumors may recur within 15 years following surgery,6 continual postoperative monitoring is recommended.
• For patients treated with somatostatin analogs, assess baseline fasting blood glucose, thyroid function tests, and heart rate. Thereafter, periodically monitor patients for adverse reactions such as GI disturbances, glucose intolerance, signs and symptoms of thyroid abnormalities, bradycardia, and arrhythmias in patients receiving long-term somatostatin analogs. Reevaluate IGF-I and GH levels at 3-month intervals to determine therapeutic response. Because the frequency of symptomatic gallstones associated with somatostatin analogs varies among studies, the need for routine ultrasound evaluation remains controversial. However, ultrasonography of the gallbladder would be indicated if the patient develops symptoms of biliary abnormalities.
Acromegaly: Patient Encounter 1: Medical History, Physical Examination, and Diagnostic Tests
EB, a 48-year-old woman, presents to a new primary care clinic. EB’s chief complaints are chronic pain of the knee and “pins and needles” and “numbness” in both hands. Over the past few years, she feels that her body has been changing. EB reports increased urinary frequency, excessive sweating, worsening headaches, an increase of two shoe sizes, and facial hair that she shaves once a week. She says that her hands have enlarged to the point that “my wedding band won’t fit anymore.”
PMH: Hypertension for 12 years, currently controlled; hyperlipidemia for 10 years, currently controlled; osteoarthritis for 5 years
FH: Mother died of colon cancer at age of 58 years. Father died of myocardial infarction at an unknown age
SH: Married, a nurse practitioner, highly educated, and physically active (bikes four times per week)
Meds: Lisinopril/hydrochlorothiazide 20/12.5 mg once daily; atorvastatin 10 mg once daily; acetaminophen 500 mg every 8 hours as needed for joint pain
ROS: (+) Coarse facial hair. Deepening of voice
PE:
VS: BP 118/76 mm Hg, P 78 bpm, RR 18 breaths/min, T 37.5°C (99.5°F)
HEENT: Ophthalmic examination reveals normal visual acuity and fields. (+) Protruding jaw and large fleshy nose
CV: RRR, normal S1, S2; no murmurs, rubs, gallops
Abd: Soft, nontender, nondistended; (+) bowel sounds, no hepatosplenomegaly
Rectal: Heme (−) stool
Labs: Electrolytes and renal function are within normal limits. Fasting blood glucose level is 206 mg/dL (11.43 mmol/L), HbA1c is 8.5%, and (-) microalbumin. GH level following an OGTT is 8 ng/mL (8 mcg/L). Elevated IGF-I level at 790 ng/mL (790 mcg/L)
MRI and CT: Both reveal a pituitary tumor approximately 5 mm in diameter.
Given this information, what signs and symptoms of acromegaly does EB exhibit?
Identify your treatment goals for EB.
What nonpharmacologic and pharmacologic treatment options are available for EB?
• For patients treated with a GH receptor antagonist, GH levels are not measured because pegvisomant is a modified GH molecule that is detected in commercial GH assays, resulting in falsely elevated GH levels. Therefore, IGF-I level is the principal biochemical marker used to assess response to pegvisomant therapy. After appropriate dose titration, monitor IGF-I levels every 6 months.6 Concern for tumor growth requires careful monitoring of tumor size; therefore, performing MRI every 6 months during the first year of therapy and annually thereafter is recommended.6 Because of abnormal liver function associated with pegvisomant therapy, it is mandatory to monitor all patients’ liver function tests prior to initiation of therapy, monthly during the first 6 months, and every 6 months thereafter.6
• For patients receiving dopamine agonists, the maximal suppression of GH and IGF-I levels may take up to 3 months to achieve. Once stable control of biochemical markers is achieved with dopamine agonists or somatostatin analogs, monitor GH and IGF-I levels annually.6
• With conventional multidose radiation therapy, the most rapid decline in GH serum levels occurs within the first 2 years; monitor GH levels at the second year and annually thereafter.6 Patients who receive single-dose radiation therapy should be evaluated at 6-month intervals because response is observed earlier.
• For patients receiving concurrent pharmacologic therapy with radiation therapy, withdraw therapies every 6 to 12 months to evaluate endogenous GH secretion and assess the development of hypopituitarism.6
• Prolonged exposure to elevated GH and IGF-I can lead to serious complications in patients with acromegaly. Aggressively manage comorbid conditions such as hypertension, diabetes, dysrhythmias, coronary artery disease, and heart failure to prevent vascular and/or neuropathic complications (Table 46–3).29
GH Deficiency
Epidemiology and Etiology
In the United States, GH deficiency affects approximately 50,000 adults, with around 6,000 new cases diagnosed annually.30 Approximately 10,000 to 15,000 children have growth failure owing to GH deficiency. Children may present with GH deficiency at any time during their developmental stages. The evaluation for GH deficiency in a short child should be deferred until appropriate exclusion of other identifiable causes of growth failure, such as hypothyroidism, chronic illness, malnutrition, genetic syndromes, and skeletal disorders. Also, several medications, such as methoxamine, isoproterenol, glucocorticoids, cimetidine, methylphenidate, and amphetamines, may induce GH insufficiency.31
Table 46–3 Assessment of Acromegaly Complications at Diagnosis and Follow-Up
Pathophysiology
GH deficiency exists when GH is absent or produced in inadequate amounts. GH deficiency may be congenital, acquired, or result from disruption of the hypothalamus–pituitary axis. GH deficiency may be an isolated condition or occasionally be accompanied by other endocrine disorder (e.g., panhypopituitarism). The diagnosis of GH deficiency remains a clinical challenge because no “gold standard” currently exists. Because GH is frequently undetectable with random sampling, a stimulation or provocative test usually is performed to confirm the diagnosis in both adults and children in whom GH deficiency is suspected. Numerous pharmacologic agents such as insulin-induced hypoglycemia, levodopa, arginine, arginine plus levodopa, arginine plus GHRH, clonidine, and glucagon have been used to stimulate the pituitary to produce GH.32 However, no single test perfectly predicts GH deficiency or displays 100% sensitivity and specificity.33 Additionally, administration of each of these tests is associated with adverse effects requiring close medical supervision. Further, current abnormal cutoffs to determine diagnosis are arbitrarily defined and lack universal consensus.32,33 With further studies, these diagnostic criteria are likely to evolve and become more accurate. In prepubertal children, measurement of IGF-I concentrations may be useful in evaluating GH deficiency, with 100% specificity and 70% to 90% sensitivity.34 In children, the diagnosis of GH deficiency is further supported if height is more than two standard deviations below the population mean (age- and sex-matched).30 Failure of linear growth is an almost universal presenting feature of childhood GH deficiency.
Acromegaly: Patient Care and Monitoring
1. Assess patient’s clinical signs and symptoms to determine severity of acromegaly.
2. Review the biochemical disease markers to assess severity of acromegaly.
3. Review the available diagnostic data to determine pituitary tumor size and location. Determine if the patient has a coexisting prolactin secreting tumor. Determine if the tumor extends toward the optic chiasm or if it is continuous on the optic tracts.
4. Assess presence of acromegaly complications. Identify any significant comorbidities associated with acromegaly that require immediate treatment or early diagnosis.
5. Determine what treatment options the patient has tried in the past.
6. Evaluate patient for presence of surgical contraindications to transsphenoidal microsurgery. Determine if the patient is able or willing to undergo surgical intervention.
7. Develop a formal plan to assess patient’s response and complications to surgical intervention. Measure both GH and IGF-I levels.
8. If surgical intervention does not achieve satisfactory disease control, select subsequent appropriate pharmacologic therapy based on patient-specific factors. In selecting therapy, be sure to consider if the patient has any contraindications or allergies to therapies.
9. Evaluate patient for presence of adverse drug reactions, drug allergies, and drug interactions.
10. Develop a plan to assess efficacy of pharmacologic therapy. Also consider if the patient’s therapy requires any dose adjustments.
11. Assess biochemical markers annually once disease control is achieved.
12. Routinely assess acromegaly complications; include blood pressure, glucose tolerance, fasting lipid profile, cardiac evaluations (if clinically indicated), colonoscopy, dual energy x-ray absorptiometry (DEXA) scan (hypogonadal only), evaluation of residual pituitary function, and evaluation of sleep apnea.
13. Provide patient education in regards to disease state, nondrug and drug therapy. Discuss with the patient:
• Possible complications of acromegaly,
• How to reduce the modifiable cardiovascular and metabolic risk factors,
• Potential effectiveness and disadvantages of existing treatment options,
• Importance of adherence to therapy, and
• Potential adverse effects that may occur.
Childhood GH deficiency may or may not continue into adulthood. Most adults with GH deficiency have overt pituitary disease and present with nonspecific clinical disorders distinct from pediatric GH deficiency, thereby making diagnosis of GH deficiency in adults more difficult than in children. Additionally, adult GH deficiency presumably is associated with increased risk of death from cardiovascular diseases.35
Treatment Goals
The goal of treatment for GH deficiency is to correct associated clinical symptoms.30 In children, prompt diagnosis and early initiation of treatment are important to maximize final adult height. In adults, efforts should be made to achieve normal physiologic GH levels in an attempt to reverse the metabolic, functional, and psychological abnormalities.32
Pharmacologic Therapy
GH Therapy
Recombinant GH therapy is the main pharmacologic treatment for GH deficiency in both children and adults. It promotes skeletal, visceral, and general body growth; stimulates protein anabolism; and affects bone, fat, and mineral metabolism2 (Table 46–1). GH therapy requires subcutaneous or intramuscular administrations. Since two-thirds of GH secretion normally occurs during sleep, it is recommended to administer injections in the evening.36Many preparations of synthetic GH are available with a variety of injection devices to make administration more appealing and easier. Protropin (somatrem) and Tev-Tropin (somatropin) are approved by the FDA for use in children, whereas other somatropin products such as Nutropin, Nutropin AQ, Humatrope, Norditropin, Genotropin, Omnitrope, and Saizen are FDA approved in both children and adults.
Although comparative trials have not been conducted to date, recombinant GH products appear to have similar efficacy for treating GH deficiency as long as the regimen follows currently approved guidelines. GH secretion decreases with age. Therefore, older adults with GH deficiency often require substantially lower replacement doses than younger individuals. The optimal therapeutic approach is to initiate GH therapy with lower doses. The recommended initial GH dose is 0.2 mg/day for young men, 0.3 mg/day for young women, and 0.1 mg/day for older adults.32 Conventional weight-based regimens are not recommended in adults due to the lack of evidence supporting higher dosages in heavier individuals and greater potential for adverse effects.32,35 Maintenance doses may be lower with chronic GH therapy.37 For elderly patients, lower GH replacement doses often are adequate because of increased GH sensitivity.32 Carefully monitor patients requiring replacement therapy with estrogens, thyroid hormones, or glucocorticoids due to potential interactions with GH therapy.32 In prepubertal children, the recommended replacement dose is 25 to 50 mcg/kg/day.38 Replacement doses should be titrated based on clinical and biochemical responses. The conversion of international units (IU or mU) to mg is a 3:1 ratio.30 Selection of an injection device depends on patient preference because there is currently no difference in clinical outcomes among the various injection systems.38
Evidence has suggested that GH treatment in GH-deficient children can increase short-term growth and improve final adult height.30 Beneficial effects of GH therapy in adults with GH deficiency have been demonstrated in subsequent studies to normalize body composition and metabolic process; improve cardiac risk profile, bone mineral density, quality of life and psychological well-being; and increase muscle strength, and exercise capacity.35Although long-term efficacy of GH replacement in adults has been demonstrated in a 10-year prospective study,37 overall reduction in mortality with GH therapy remains to be established.
Clinical Presentation and Diagnosis of GH Deficiency in Children
General
The patient will have a physical height that is greater than two standard deviations below the population mean for a given age and gender.
Signs
• The patient will present with reduced growth velocity and delayed skeletal maturation.
• Children with GH-deficient or GH-insufficient short stature also may present with abdominal obesity, prominence of the forehead, and immaturity of the face.
Laboratory Tests
• Patients will exhibit a peak GH level of less than 10 ng/mL (10 mcg/L) following a GH stimulation test.
• Reduced IGF-I concentration also may be present.
• Because GH deficiency may be accompanied by the loss of other pituitary hormones, hypoglycemia and hypothyroidism also may be noted.
Other Diagnostic Tests
• Perform MRI or CT of the hypothalamic-pituitary region to detect structural or developmental anomaly.
• Perform x-ray of left wrist and hand for children over 1 year of age to estimate bone age (knee and ankle for children younger than 1 year of age).
Adapted from Sheehan AH, Yanovski JA, Calis KA. Pituitary Gland Disorders. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy. A Pathophysiologic Approach. 7th ed. New York: McGraw Hill, 2008:1288.
From Refs. 8, 30.
Clinical Presentation and Diagnosis of GH Deficiency in Adults
General
The patient likely will have a history of childhood-onset GH deficiency, hypothalamic or pituitary disorder, or the presence of three or four other pituitary hormone deficiencies caused by head trauma, tumor, infiltrative diseases, surgery, or radiation therapy.
Symptoms
• Reduced strength and exercise capacity
• Defective sweating
• Psychological problems
• Low self-esteem
• Depression
• Fatigue/listlessness
• Sleep disturbance
• Anxiety
• Social isolation
• Emotional lability and impaired self-control
• Poor marital and socioeconomic performance
Signs
• Increased fat mass (especially abdominal obesity)
• Reduced lean body mass
• Reduced muscle strength
• Reduced exercise performance
• Thin, dry skin; cool peripheries; poor venous access
• Depressed affect, labile emotions
• Impaired cardiac function
Laboratory Tests
• Patients will exhibit a peak GH level of less than 5 ng/mL (5 mcg/L) following a GH stimulation test.
• Low or low-normal IGF-I level also may be present.
• Increased low-density lipoprotein cholesterol, total cholesterol, triglycerides; decreased high-density lipoprotein cholesterol.
• Reduced bone mineral density associated with an increased risk of fracture.
• Increased insulin resistance and increased prevalence of impaired glucose tolerance.
• GH deficiency may be accompanied by the loss of other pituitary hormones.
From Refs. 32, 35, 36.
Begin GH therapy as soon as possible to optimize long-term growth, especially for young children in whom GH deficiency is complicated by fasting hypoglycemia.30 Selection of the optimal GH replacement dose will need to be individualized depending on response, financial resources, and product availability. Although the appropriate time to discontinue therapy remains controversial in childhood GH deficiency, it is reasonable to continue GH replacement until either the child has reached satisfactory adult height, achieved documented epiphyseal closure, or failed to respond to therapy.30 Management of the transition between pediatric and adult GH replacement remains a challenge because there are no current data to indicate the correct approach. Starting GH therapy at a low dose and gradually titrating upward may decrease the potential for adverse effects. The need for GH replacement therapy may be lifelong.
Children treated with GH replacement therapy rarely experience significant adverse effects, whereas adults are more susceptible to dose-related adverse effects. Treatment with GH may mask underlying central hypothyroidism and adrenal insufficiency. GH-induced symptoms, such as edema, arthralgia, myalgia, and carpal tunnel syndrome, are common and necessitate dose reductions in up to 40% of adults. Benign increases in intracranial pressure may occur with GH therapy and generally are reversible with discontinuation of treatment. Often, GH therapy can be restarted with smaller doses without symptom recurrence.
In rapidly growing children, a slipped capital femoral epiphysis may occur when the head of the femur shifts in a backward direction.38 There is no evidence that this problem is caused by GH therapy, but any child who experiences a change in gait during treatment should be evaluated by an orthopedic surgeon.38 Treatment with GH may induce insulin resistance and lead to the development of glucose intolerance in patients with pre-existing risk factors. Presently, there is no compelling evidence that GH replacement therapy is associated with an increased risk of leukemia, solid tumor, or tumor recurrence.30,32However, in children with a history of malignancies, it would be prudent to wait for a 1-year tumor-free period (5 years for adults) before initiating GH therapy.30 Any patients treated for a prior malignancy may be at risk for a second malignancy and should be monitored carefully for tumor recurrence.30 Other rare findings associated with GH replacement therapy include breast development, pancreatitis, juvenile osteochondritis (inflammation of a bone and its cartilage), worsening of scoliosis, and increased pigmentation.38 Because deaths have been reported with use of GH in children with Prader-Willi syndrome who are severely obese or suffer from respiratory impairments, use of GH is contraindicated in these individuals.
Insulin-Like Growth Factor I Therapy
Mecasermin (Increlex) is the only recombinant IGF-I replacement therapy for the treatment of growth failure in children with severe primary IGF-I deficiency or with GH gene deletions who have developed neutralizing antibodies to GH. This product has not been evaluated in patients with GH deficiency aside from the genetic abnormalities.
Outcome Evaluation
• Children with GH deficiency should be evaluated by a pediatric endocrinologist every 3 to 6 months. Monitor for an increase in height and change in height velocity to assess response to GH therapy30,38Every effort should be made to maximize height before the onset of puberty. Once final adult height is reached and GH is discontinued for at least 1 month, retest and reevaluate the patient using the adult GH-deficiency diagnostic criteria.38
• Assess patients with scoliosis for further curvature of the spine.
• Although GH and IGF-I levels do not always correlate with growth response, measure IGF-I levels yearly to assess adherence to therapy and patient response. If the IGF-I levels are substantially above the normal range 2 years after GH replacement therapy, the dose should be reduced.38 IGF-I level may be used as a guide to gradually reduce replacement dose after epiphyseal closure.
• Routine monitoring of fasting lipid profile, bone mineral density, and body composition in children is not typically required during GH replacement but should be done before and after discontinuation of therapy.30,38
• In adults, measurement of serum IGF-I, along with careful clinical evaluation, appears to be the most reliable way to assess the appropriateness of the GH dose. Measure IGF-I serum concentrations annually and 6 weeks following dosage adjustments.35
• Continuously monitor for dose-related adverse effects such as edema, arthralgia, myalgia, and carpal tunnel syndrome.
• Evaluate psychological well-being. Assess patient’s bone mineral density every 2 years. Measure body composition, metabolic status, and cardiac risks (e.g., fasting lipid profile) yearly.32
• Patients with a history of cancer or those at risk for malignancy should be monitored closely.
• Measure a free thyroxine serum concentration at baseline and at 6- to 12-month intervals thereafter.30
• Measure fasting blood glucose levels at baseline and annually to assess for glucose intolerance.35
PROLACTIN
Prolactin is an essential hormone for normal production of breast milk following childbirth. It also plays a pivotal role in a variety of reproductive functions. Prolactin is regulated primarily by the hypothalamus-pituitary axis and secreted solely by the lactotroph cells of the anterior pituitary gland. Under normal conditions, secretion of prolactin is predominantly under inhibitory control by dopamine and acts on the D2 receptors located on the lactotroph cells. Increase of hypothalamic thyrotropin-releasing hormone in primary hypothyroidism can stimulate the release of prolactin.
GH Deficiency in Children: Patient Care and Monitoring
1. Assess child’s growth characteristics, and compare physical height with a population standard (e.g., Centers for Disease Control and Prevention Growth Charts).
2. Obtain a thorough history and physical examination that may indicate the possible presence of GH deficiency. Exclude other identifiable causes of growth failure, such as hypothyroidism, chronic illness, malnutrition, genetic syndromes, and skeletal disorders.
3. Perform imaging tests of the hypothalamic-pituitary region to detect structural or developmental anomalies. Perform x-ray of the wrist and hand to estimate bone age.
4. Perform a provocative test to measure GH and IGF-I levels.
5. Initiate GH replacement therapy based on patient preference. Make sure that the child does not have any contraindications to GH therapy.
6. Develop a formal plan to assess response (increase in height and change in height velocity) and adverse effects of GH replacement therapy. Make dosage adjustments when appropriate.
7. May continue GH replacement therapy until child reaches satisfactory adult height, achieves documented epiphyseal closure, or fails to respond to treatment.
8. Review and retest the child using adult GH deficiency diagnostic criteria once the child reaches final adult height.
9. Provide patient education in regard to disease state and drug therapy. Discuss with the child and parents:
• GH deficiency
• Potential effectiveness and disadvantages of existing GH replacement therapy
• Importance of adherence to therapy
• Potential for adverse effects or need for lifelong replacement
GH Deficiency in Adults: Patient Care and Monitoring
1. Assess patient’s clinical signs and symptoms to determine severity of GH deficiency.
2. Perform a provocative test to measure GH and IGF-I levels.
3. Evaluate the patient for the presence of metabolic abnormalities and cardiovascular and fracture risks.
4. Initiate GH replacement therapy based on patient preference. Make sure that the patient does not have any contraindications to GH therapy.
5. Develop a plan to assess the efficacy and adverse effects of GH therapy, and consider if the patient’s therapy requires any dose adjustments based on IGF-I level, patient response, and adverse effects.
6. Provide patient education in regard to disease state and drug therapy. Discuss with the patient:
• Possible complications of GH deficiency
• How to reduce the modifiable cardiovascular and metabolic risk factors
• Potential disadvantages and effectiveness of existing GH replacement therapy
• Importance of adherence to therapy
• Potential for adverse effects or need for lifelong replacement
Hyperprolactinemia
Epidemiology and Etiology
Hyperprolactinemia affects women of reproductive age more than men. Although this disorder occurs in less than 1% of the general population, the estimated prevalence in women with reproductive disorders (e.g., amenorrhea) is as high as 15% to 43%.39 Numerous etiologies of hyperprolactinemia are presented in Table 46–4.39 Any medications that antagonize dopamine or stimulate prolactin release can induce hyperprolactinemia.8,31,39,40 Therefore, it is important to exclude medication-induced hyperprolactinemia from other common causes such as pregnancy, primary hypothyroidism, benign prolactin-secreting pituitary adenoma (prolactinoma), and renal insufficiency. Prolactinomas are the most common pituitary tumors. They are classified as microprolactinomas if they are less than 10 mm in diameter and as macroprolactinomas if they are 10 mm or greater in diameter.40 In general, microprolactinomas rarely increase in size, whereas macroprolactinomas have the potential to enlarge and invade the surrounding tissues.41
Pathophysiology
Hyperprolactinemia is a condition of elevated serum prolactin.40 It is the most common endocrine disorder of the hypothalamic–pituitary axis. High prolactin levels inhibit the release of gonadotropin-releasing hormone by the hypothalamus and subsequently suppress secretion of LH and FSH from the anterior pituitary. High prolactin levels result in reduced gonadal hormone levels, often leading to reproductive dysfunction and galactorrhea (inappropriate breast milk production).
Table 46–4 Causes of Hyperprolactinemia
Physiologic Causes
Pregnancy
Stress (including exercise and hypoglycemia)
Breast stimulation
Breast-feeding
Coitus
Sleep
Meal
Increased Prolactin Production
Ovarian: polycystic ovarian syndrome
Oophorectomy (removal of an ovary)
Pituitary tumors:
Adenomas
Microprolactinoma (less than 10 mm diameter)
Macroprolactinoma (greater than or equal to 10 mm diameter)
Hypothalamic stalk interruption (prevent dopamine from reaching the pituitary)
Hypophysitis (inflammation)
Ectopic tumors
Hypothalamic Prolactin Stimulation
Primary hypothyroidism
Adrenal insufficiency
Reduced Prolactin Elimination
Chronic renal failure
Hepatic cirrhosis
Neurogenic Causes
Chest-wall injury (e.g., surgery, herpes zoster)
Spinal cord lesions
Abnormal Molecules
Macroprolactinemia
Medications
Dopamine antagonists: antipsychoticsa; phenothiazines; metoclopramide; domperidone
Dopamine-depleting agents: reserpine; a-methyldopa
Prolactin stimulators: serotonin reuptake inhibitors; dexfenfluramine; estrogens; progestins; antiandrogens; gonadotropin-releasing hormone analogs; benzodiazepines; tricyclic antidepressants; monoamine oxidase inhibitors; protease inhibitors; histamine2 receptor antagonists
Other: isoniazid; cocaine; opioids; verapamil
Seizures
Idiopathic (Unknown)
a Atypicals (olanzapine and clozapine) other than risperidone may cause an early but transient elevation in prolactin.
Adapted in part, with permission, from Sheehan AH, Yanovski JA, Calis KA. Pituitary gland disorders. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy. A Pathophysiologic Approach. 7th ed. New York: McGraw Hill, 2008:1291.
From Refs. 8, 31, 39, 40, 42.
In combination with clinical symptoms, at least three repeated measures of serum prolactin levels greater than 20 ng mL (20 mcg/L) are needed to confirm the diagnosis. A number of physiologic factors such as eating, exercise, and stress can transiently elevate prolactin levels.8 Therefore, prolactin measurements should be obtained at rest, preferably in the morning under fasting conditions.39 If an IV line is present or planned, it is prudent to wait at least 2 hours after line insertion before measuring serum prolactin to decrease detecting transient physiologic increases in prolactin level39,42 (Table 46–4). Medication-induced hyperprolacti-nemia typically is associated with prolactin levels of less than 150 ng/mL (150 mcg/L), whereas prolactin levels greater than 250 ng/mL (250 mcg/L) are almost always associated with macroprolactinoma.43
Treatment Goals for Hyperprolactinemia
Because hyperprolactinemia is often associated with hypo-gonadism, the goals for management of hyperprolactinemia are to restore the clinical consequences of hypogonadism and reduce its associated risk for osteoporosis, as follows42:
• Normalize prolactin level
• Improve clinical symptoms
• Restore normal fertility
• Restore and maintain normal gonadal function
• Protect against development of osteoporosis
• Prevent disease recurrence
• If a pituitary tumor is present:
• Ablate or reduce tumor size to relieve tumor mass effect
• Preserve normal pituitary function
Clinical Presentation and Diagnosis of Hyperprolactinemia
General
Hyperprolactinemia most commonly affects women of reproductive age and is very rare in men.
Signs and Symptoms
Premenopausal women:
• Headache and compromised or loss of vision caused by the prolactin-secreting tumor and its close proximity to the optic structures.
• Clinical presentation is associated with the degree of prolactin elevation:
• Prolactin greater than 100 ng/mL (100 mcg/L): hypogonadism, galactorrhea, and amenorrhea
• Prolactin 51 to 75 ng/mL (51–75 mcg/L): oligomenorrhea (infrequent menstruation).
• Prolactin 31 to 50 ng/mL (31–50 mcg/L): decreased libido and infertility.
• Increased body weight may be associated with prolactin-secreting pituitary tumor.
• The degree of hypogonadism generally is proportionate to the degree of prolactin elevation.
• Excessive hair growth (hirsutism) and acne also may be present owing to relative androgen excess compared with low estrogen levels.
Men:
• Decreased libido, decreased energy, erectile dysfunction, impotence, decreased sperm production, infertility, gynecomastia, and rarely, galactorrhea.
• Impotence is unresponsive to treatment and is associated with reduced muscle mass, loss of pubic hair, and osteoporosis.
Laboratory Tests
• Prolactin serum concentrations at rest will be greater than 20 ng/mL (20 mcg/L) in men or 25 ng/mL (25 mcg/L) in women with at least three measurements.
• Obtain β-human chorionic gonadotropin level to exclude pregnancy.
• Obtain TSH level to exclude primary hypothyroidism.
• Obtain blood urea nitrogen and serum creatinine tests to exclude renal failure.
Other Diagnostic Tests
• Perform MRI to locate the tumor, exclude a pseudoprolactinoma, and validate the diagnosis.
• Consider a bone mineral density test in patients with long-term hypogonadism.
Additional Clinical Sequelae
• The prolonged suppression of estrogen in premenopausal women with hyperprolactinemia leads to decreases in bone mineral density and significant risk for the development of osteoporosis.
• Risk for ischemic heart disease may be increased with untreated hyperprolactinemia.
Adapted, with permission, from Sheehan AH, Yanovski JA, Calis KA. Pituitary gland disorders. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy. A Pathophysiologic Approach. 7th ed. New York: McGraw Hill, 2008:1291.
From Refs. 8, 40, 42.
• Prevent progression of pituitary tumor or hypothalamic disease
General Approaches to Treatment
Management of drug-induced hyperprolactinemia is to discontinue the offending agent, if possible, and start an appropriate therapeutic alternative. In situations where the offending agent cannot be discontinued, cautious use of hormone replacement, biphosphonate therapy, and/or dopamine agonists may be considered depending on the patient’s clinical circumstances.44 Treatment options for the management of hyperprolactinemia include: (a) clinical observation; (b) pharmacologic therapy with dopamine agonists; (c) transsphenoidal pituitary adenomectomy; and (d) radiation therapy. Figure 46–4outlines an approach to the management of hyperprolactinemia after excluding drug-induced causes and other etiologies (e.g., hypothyroidism, renal failure, hepatic dysfunction).42 Clinical observation and close monitoring are justifiable in patients with asymptomatic elevation of prolactin. Dopamine agonists are the first-line treatment of choice for all patients with hyperprolactinemia; transsphenoidal surgery and radiation therapy are reserved for patients who are resistant to or severely intolerant of pharmacologic therapy.39
Pharmacologic Therapy
Dopamine is the principal neurotransmitter responsible for the inhibition of prolactin secretion from the anterior pituitary. Thus, dopamine agonists are the main pharmacologic therapy used for management of hyperprolactinemia.40Treatment with dopamine agonists has proven to be extremely effective in normalizing serum prolactin level, restoring gonadal function, decreasing tumor size, and improving visual fields.40 Patients with macroprolactinomas generally require a higher dose to normalize prolactin levels compared with patients with microprolactinomas.43
Two dopamine agonists are used for the management of hyperprolactinemia, bromocriptine, and cabergoline (Table 46–5).39,45 Because these two dopamine agonists are ergot derivatives, they are contraindicated in combination with potent cytochrome P-450 subfamily IIIA polypeptide 4 (CYP3A4) inhibitors, including protease inhibitors (e.g., ritonavir and indinavir), azole antifungals (e.g., ketoconazole and itraconazole), and some macrolide antibiotics (e.g., erythromycin and clarithromycin). Furthermore, ergot derivatives can cause constriction of peripheral and cranial blood vessels. These medications are also contraindicated in patients with uncontrolled hypertension, severe ischemic heart disease, or peripheral vascular disorders. Caution should be exercised with concomitant use of other ergot derivates and in patients with impaired renal or hepatic function, dementia, concurrent antihypertensive therapy, or a history of psychosis, peptic ulcer disease, or cardiovascular disease.
Bromocriptine
Bromocriptine directly binds to the D2 receptors on the lactotroph cells to exert its effect. Bromocriptine normalizes prolactin level in more than 90% of patients, restores menstrual cycles, and reduces tumor size in 62% of patients.39Adverse effects such as nausea, dizziness, and orthostatic hypotension often limit 5% to 10% of patients from continuing treatment. Thus, start bromocriptine at a low dose (e.g., 0.625–1.25 mg) at bedtime (taken with a snack) to decrease adverse effects.41 Slowly titrate up to the optimal therapeutic dose (2.5-15 mg/day) because most adverse effects subside with continual treatment.43If the adverse GI effects are not tolerable, bromocriptine can be administered vaginally at a reduced dose (2.5 mg/day).46 Owing to its short half-life of only 6 hours, bromocriptine must be administered in divided doses, which may compromise patient adherence.
Cabergoline
Cabergoline has a higher affinity for D2 receptors than bromocriptine. It is a long-acting dopamine agonist capable of inhibiting pituitary prolactin secretion for at least 7 days after a single oral dose.45 The prolonged duration of action allows for once- or twice-weekly administration. Cabergoline appears to be significantly better tolerated than bromocriptine.39 Transient elevations of serum alkaline phosphatase, bilirubin, and aminotransferases have been reported in a few patients treated with cabergoline. Cabergoline is more effective in normalizing prolactin levels and restoring menses than bromocriptine.45 It also may be effective in treating hyperprolactinemia in patients who are resistant to or intolerant of bromocriptine and in men and women with micro- and macroprolactinomas.39 Given its favorable safety and efficacy profile and ease of administration, cabergoline has replaced bromocriptine as first-line therapy for the management of hyperprolactinemia.40 Withdrawal of pergolide from the U.S. market due to increased risk for valvular heart disease raised concerns about the safety of cabergoline. In patients with prolactinomas, tricuspid regurgitation was associated with higher cabergoline cumulative dose of more than 280 mg.47 However, recent studies suggest the lower doses of cabergoline commonly used in the management of hyperprolactinemia do not appear to increase the risk of clinically significant valvular heart diseases.48,49
Nonpharmacologic Therapy
In a small number of patients who have failed or are intolerant of dopamine agonists, transsphenoidal adenomectomy may be necessary. Surgical treatment is also considered in patients with nonprolactin-secreting tumors or macroprolactinomas that jeopardize the optic chiasm.40 Nonetheless, surgical intervention does not reliably lead to long-term cure and may cause permanent complications.42 Radiation therapy is reserved for failures of both pharmacologic therapy and surgery.40 However, normalization of prolactin levels with radiation therapy may take 10 years to show full benefit, and radiation-induced hypopituitarism may require lifelong hormone replacement.
Management of Hyperprolactinemia in Pregnancy
Most women with hyperprolactinemia require dopamine agonist therapy to achieve regular ovulatory cycles and pregnancy. Since restoration of the ovulatory cycle may occur within 1 week of initiating therapy, it is necessary to caution patients regarding their potential to become pregnant.50
FIGURE 46–4. Management of hyperprolactinemia. (From Ref. 42.)
Overall, there is reassuring worldwide experience that bromocriptine use during pregnancy does not increase fetal malformations, spontaneous miscarriage, ectopic pregnancy, or multiple births.39,41Furthermore, no teratogenic effects have been reported in women who received cabergoline during the first and second trimesters of pregnancy.41,45 Despite these data, women who become pregnant while on a dopamine agonist should discontinue treatment immediately to minimize fetal exposure. Because cabergoline has a prolonged half-life, women who plan to become pregnant should discontinue the drug at least 1 month before planned conception.45
Microadenomas rarely cause complications during pregnancy. However, untreated macroprolactinomas carry about 15% to 35% risk of tumor enlargement and potentially can jeopardize vision.43 Therefore, monitor women with macroprolactinomas closely for the development of headache and visual impairments. Baseline and routine visual field examinations are essential. Evidence of abnormal visual fields may indicate tumor growth and should be followed by an MRI. Should tumors enlarge, bromocriptine is the preferred choice over cabergoline because of greater experience with this drug during pregnancy.41,50
Table 46–5 Comparison of Dopamine Agonists for Treatment of Hyperprolactemia
Hyperprolactinemia: Patient Encounter 2: Medical History, Physical Examination, and Diagnostic Tests
WB, a 27-year-old woman, presents to the Women’s Health Clinic. Her chief complaint is milky fluid discharge from both breasts. WB also mentions that her menstrual periods have stopped since she stopped taking her oral contraceptive 8 months ago with the hope of conceiving. Her menstrual cycle was regular before starting the oral contraceptive. WB does not have recent weight change, excessive hair growth, or acne. She also does not exercise excessively and is otherwise healthy. She took a home pregnancy test 1 week ago, which was negative.
PMH: None
FM: Both parents are still alive and healthy.
SH: Married, works as a high school teacher, and is physically active (walks 3 miles twice a week)
Meds: NuvaRing use as directed (discontinued 8 months ago); acetaminophen 325 mg two tablets every 4 to 6 hours as needed for mild headaches
ROS: Negative, other than in history of present illness.
PE:
HEENT: Ophthalmic examination reveals normal visual acuity and fields. (–) goiter
VS: BP 100/62 mm Hg, P 82 bpm, RR 18 breaths/min, T 37.1°C (98.8°F)
CV: RRR, normal S1, S2; no murmurs, rubs, or gallops
Breasts: (+) bilateral expressible galactorrhea with no other abnormality
Abd: Soft, nontender, nondistended; (+) bowel sounds; no hepatosplenomegaly
Rectal: Heme (−) stool
Labs: Electrolytes, renal and thyroid function, FSH, LH, and testosterone are within normal limits. Elevated prolactin at 115 ng/mL (115 mcg/L). Pregnancy test is negative.
Imaging: MRI reveals a pituitary tumor approximately 9 mm in diameter.
Given this information, what signs and symptoms does WB have for hyperprolactinemia?
Identify your treatment goals for WB.
What nonpharmacologic and pharmacologic treatment options are available for WB?
Outcome Evaluation
• Assess patients for tolerability to dopamine agonists.
• Monitor clinical symptoms associated with hyperprolactinemia every month for the first 3 months to assess therapeutic efficacy and assist with dose titration.
• Evaluate the patient for symptoms, such as headache, visual disturbances, menstrual cycles in women, and sexual function in men, to assess clinical response to therapy.
• Once the prolactin level is normalized and clinical symptoms of hyperprolactinemia have resolved, monitor prolactin level every 6 to 12 months.42,43
Hyperprolactinemia: Patient Care and Monitoring
1. Assess patient’s clinical signs and symptoms of hyperprolactinemia.
2. Review the available diagnostic data to determine severity and exclude other common causes of hyperprolactinemia.
3. Obtain a thorough medication history to exclude medication-induced hyperprolactinemia.
4. Determine patient’s plan regarding pregnancy because this influences treatment.
5. Educate patient about safety and efficacy of dopamine agonists. Make sure that the patient does not have any contraindications or allergies to drug therapies.
6. Develop a formal plan to assess response and adverse effects of dopamine agonists. When appropriate, be sure to make dose adjustments.
7. If the prolactin level remains normal for 2 years, reassess the need to continue treatment. Make sure that the patient is taking the lowest effective dose for management of hyperprolactinemia.
8. Provide patient education in regard to disease state and nondrug and drug therapy. Discuss with the patient:
• Risk factors associated with hyperprolactinemia
• Potential disadvantages and effectiveness of existing dopamine agonist therapy
• Potential disadvantages and effectiveness of surgery and radiation treatment
• Importance of adherence to therapy
• Potential for adverse effects or long-term complications
• Evaluate visual fields in pregnant patients every 2 to 3 months.40
• If the prolactin level is well controlled with dopamine agonist therapy for 2 to 3 years, gradually taper therapy to the lowest effective dose.40 Check prolactin levels after each dose reduction.
• If the prolactin levels remain unchanged for 1 year at the reduced dose, dopamine agonist therapy may be discontinued.
• It is essential to monitor prolactin levels every 6 months or annually to detect the possibility of permanent remission of pituitary disease.42
• The need to continue dopamine agonists in postmenopausal women with microprolactinomas must be reassessed because these patients have a higher probability of maintaining normal prolactin levels after treatment is discontinued.40
• In patients with macroprolactinomas, monitor visual field at baseline and repeat the test 1 month after initiation of a dopamine agonist.
• Repeat the MRI 6 months after initiating therapy, or if an increase in symptoms, or rise in prolactin levels suggests the presence of tumor growth.43
• Discontinuation of therapy in patients with macropro-lactinomas usually leads to tumor regrowth and recurrence of hyperprolactinemia. This decision warrants careful consideration.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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