Pituitary adenomas are one of the most common intracranial neoplasms with a prevalence of approximately 10% discovered at autopsy (Arafah & Nasrallah, 2001). The number of clinically discovered tumors is estimated to be lower than the number found during autopsy. Pituitary adenomas are classified as either secreting (secrete hormones) or nonsecreting (do not secrete hormones). Examples of secreted hormones include prolactin, adrenocorticotropic hormone (ACTH), and growth hormone (GH). Transsphenoidal surgery is often the first line of treatment for most secreting adenomas (Greenberg, 2001). However, nonsurgical options are also needed because many patients experience a reoccurrence of tumors after surgery, some patients are not candidates for surgery, and other patients choose not to undergo a surgical procedure at all. Pharmacological management is an important strategy in addressing these situations because secreting tumors often can be treated with medication. This article describes the endocrine effects of secreting pituitary tumors and how such tumors can be managed pharmacologically.
Endocrine Effects
The most common secreting adenomas are prolactinomas (Serri, Chik, Ur, & Ezzat, 2003), which secrete the hormone prolactin. These tumors can cause impotence in males and infertility in either sex. Men commonly present with symptoms of mass effect and experience galactorrhea or gynecomastia in less than 20%-30% of cases (Pickett, 2003). Oligomenorrhea or amenorrhea is the primary symptom in women. About 90% of women will experience galactorrhea, for which they frequently seek medical help (Pickett).
Adenomas that secrete ACTH cause Cushing's disease, an endogenous hypercortisolism. Common signs of Cushing's disease are weight gain and hypertension. Other signs and symptoms are purple striae, hyperglycemia, amenorrhea in women, impotence in men, reduced libido in both sexes, and hypokalemic alkalosis. Complications of Cushing's disease include atrophic skin, tissue-paper-thin skin with easy bruising, poor wound healing, psychosis, mood changes, depression, emotional lability, dementia, osteoporosis, muscle wasting, hirsutism, and acne.
About 20% of pituitary tumors can cause acromegaly (Arafah & Nasrallah, 2001); these tumors produce an excess of GH. GH is controlled by the hypothalamus, which secretes both a releasing hormone (growth hormone releasing hormone, GHRH) and an inhibitory hormone (growth hormone inhibiting hormone, GHIH, or somatostatin) into the hypothalamo-hypophyseal portal system. GHRH stimulates pituitary secretion and synthesis of GH in the pituitary and induces GH gene transcription. An effect of GH is the secretion from the liver of insulin-like growth factor-1 (IGF-1), a protein also called somatomedin-C, which is responsible for most symptoms of acromegaly due to its growth-promoting effects. These effects are actually due to IGF-1 acting on target cells in bone and muscle. IGF-1 is usually elevated in patients with acromegaly (Greenberg, 2001; Arafah & Nasrallah; Sachse, 2001).
Some common physical characteristics seen in acromegaly are skeletal deformities such as increasing hand and foot size, thickening of the heel pad, frontal bossing, prognathism (a protrusion of the jaw caused by malformations of the bones of the face), and macroglossia (an enlargement of the tongue). Other signs and symptoms include hypertension, soft tissue swelling, carpal tunnel syndrome, debilitating headaches, excessive perspiration (especially palmar hyperhidrosis), oily skin, joint pain, and fatigue. Patients with acromegaly are also at greater risk for colon cancer (Arafah & Nasrallah, 2001), and those with elevated GH levels have two to three times the expected mortality rate compared to the healthy population. In children, elevated levels of GH before closure of the epiphyseal plates in the long bones produce a condition called gigantism rather than acromegaly.
Treatment of Prolactin-Secreting Adenomas
Medications to treat prolactin-secreting adenomas include bromocriptine, pergolide, and cabergoline. Medication ranges and costs for all medical treatments of prolactin-secreting adenomas are summarized in Table 1.
Bromocriptine is a semisynthetic ergot alkaloid that binds to receptors on normal and tumor lactotrophs and inhibits the synthesis and secretion of prolactin. It lowers the prolactin level, regardless of the source, to <10% of pretreatment values in most patients (Greenberg, 2001). Bromocriptine has been shown to reduce tumor size in 3-6 weeks in 70% of patients with prolactin-secreting macroadenomas, but this effect lasts only as long as therapy is maintained (Arafah & Nasrallah, 2001). With microadenomas, therapy may be continued for 5-6 years, then be slowly tapered off and eventually even be discontinued. If prolactin levels increase during this process, the dosage can be increased and prolonged (Arafah & Nasrallah).
Bromocriptine is not effective in all patients as 1% of tumors still continue to grow and can enlarge rapidly upon abrupt discontinuation. Prolonged treatment may reduce the surgical cure rate as it has been shown that one year of treatment with bromocriptine has reduced the surgical cure rate by 50%, possibly because of induced fibrosis (Greenberg, 2001). Other literature suggests that pharmacological therapy should be the primary treatment for most patients with prolactinomas (Arafah & Nasrallah, 2001).
Bromocriptine is started at 0.625 mg orally and taken right before bed with food to help reduce side effects. After one week, a morning dose of 1.25 mg is added. At appropriate intervals, the dose is increased by 1.25 mg increments. Prolactin levels are checked after 1 month and the dosage is changed accordingly. Dosage changes are usually made every 2 to 5 weeks for microadenomas and every 3 to 4 days for macroadenomas causing mass effects. The usual dosage needed to restore menses is between 5 mg and 7.5 mg per day, with a range of 2.5-15 mg (Schlechte, 2003). Patients with persistent hyperprolactinemia should be given the highest tolerable dose recommended (Arafah & Nasrallah, 2001). The drug may be given in a single dose or in divided doses up to three times a day. It may be necessary to administer a higher dose initially for approximately 6 months and then lower the dose to maintain normal prolactin levels. The half-life for bromocriptine is 4-41/2 hours in the initial phase and 45-50 hours in the terminal phase. It is metabolized in the liver and excreted principally in feces via biliary elimination (McEvoy, Miller, & Litvak, 2005). Bromocriptine is contraindicated in those with uncontrolled hypertension or toxemia of pregnancy and in those who are sensitive to any ergot alkaloid (McEvoy et al.). Common reactions to bromocriptine include nausea, headache, dizziness, fatigue, vomiting, abdominal pain, nasal congestion, constipation, diarrhea, drowsiness, orthostatic hypotension, anorexia, dry mouth, dyspepsia, involuntary movements, visual disturbances, hallucinations, and gastrointestinal (GI) bleeding. Serious reactions to bromocriptine are seizures, stroke, and myocardial infarction (ePocrates Rx, 2005).
Pergolide is a long-acting ergot alkaloid dopamine agonist that reduces prolactin levels but is not approved by the Food and Drug Administration (FDA) for hyperprolactinemia. The dosage starts at 0.05 mg orally at bedtime and is increased by 0.025-0.05 mg increments (up to a maximum of 0.25 mg per day) until desired prolactin levels are achieved. Because pergolide allows once-daily dosing, it also may improve compliance (Greenberg, 2001). Pergolide undergoes extensive enterohepatic metabolism (McEvoy et al., 2005). However, knowledge of the exact pharmacokinetics is limited. Contraindications would be a known hypersensitivity to the drug or to ergot derivatives. Common reactions include dyskinesias, nausea, dizziness, hallucinations, rhinitis, dystonia, confusion, constipation, somnolence, orthostatic hypotension, insomnia, peripheral edema, pain, diarrhea, anxiety, dyspepsia, visual abnormalities, anorexia, dry mouth, and rash. Serious reactions are hallucinations, psychosis, sudden sleep episodes (Traynor, 2003), severe hypotension, hypertension, arrhythmias, myocardial infarction, blood dyscrasias, cholelithiasis, and hepatitis. Rare and serious reactions include pleuritis, pleura effusion, pleural fibrosis, pericarditis, pericardial effusion, cardiac valvulopathy, and retroperitoneal fibrosis (ePocrates Rx, 2005).
Cabergoline is an ergot alkaline derivative that is a selective D2 dopamine agonist which suppresses prolactin for more than 14 days with a single dose. The elimination half-life is 60-100 hours, which permits dosing 1-2 times weekly. Cabergoline controls prolactin levels and allows resumption of the ovulatory cycles (Greenberg, 2001). Theoretically, cabergoline is more effective than bromocriptine because of its longer half-life and greater specificity for D2 receptors (Arafah & Nasrallah, 2001). Side effects include headache and gastrointestinal symptoms, which are less problematic than with bromocriptine. Side effects of all the ergot alkaline derivative drugs are dose related and the medications should be started slowly, increased as needed, and given with food. Dosing starts with 0.25 mg orally twice weekly and is increased by 0.25 mg per dose every 4 weeks as needed to control prolactin levels (maximum of 3 mg per week). The typical dose is 0.5-1 mg twice weekly. It is possible to combine the total dose and give it once weekly. Contraindications to the use of this drug include eclampsia or preeclampsia (it is safe in the second or third trimesters with no evidence of risk) and uncontrolled hypertenstion. The drug is metabolized in the liver, and dosage should be reduced with severe hepatic dysfunction. Common adverse effects are nausea, vomiting, headache, dizziness, constipation, weakness, abdominal pain, dyspepsia, fatigue, vertigo, hot flashes, depression, dry mouth, and orthostatic hypotension (ePocrates Rx, 2005). The only noted serious reaction is orthostatic hypotension.
Fertility can be restored with all three of these drugs (Schlechte, 2003). Women should use a mechanical form of contraception for several months until two or three normal menstrual cycles have occurred. This precaution will help patients recognize when pregnancy occurs and minimize the use of dopamine agonists while pregnant. Bromocriptine should be stopped when one menstrual cycle has been missed (Schlechte). If bromocriptine is continued during pregnancy, it does cross the placenta and suppresses fetal prolactin secretion, but it has not been associated with fetal abnormalities (Arafah & Nasrallah, 2001). Pregnancy, however, can cause a 1% tumor enlargement (Schlechte).
Other drugs used for treatment of prolactinomas that have not been approved by the FDA include mesylate, lisuride and quinagolide (Shimon & Melmed, 1998). Healthcare professionals may see these drugs used in the future as treatment for prolactinomas.
Treatment of ACTH-Secreting Adenomas
Transsphenoidal adenomectomy is the treatment of choice for ACTH-secreting adenomas, but pharmacological therapy may be used for several weeks prior to surgery to control significant manifestations of hypercortisolism (such as diabetes, hypertension, and psychiatric disturbances). Available medications include ketoconazole, aminoglutethimide, metyrapone, mitotane, and cyproheptadine. Table 1 summarizes the dosing ranges and costs for these treatments.
Ketoconazole, an antifungal agent that blocks adrenal steroid synthesis, is the initial drug used to treat ACTHsecreting adenomas. Over 75% of patients achieve normal levels of urinary free cortisol and 17-hydroxycorticosteroid while on ketoconazole (Greenberg, 2001). Dosing starts with 200 mg taken orally twice a day and the dosage is adjusted based on 24-hour levels of urine free cortisol and 17-hydroxycorticosteroid. The usual maintenance dose is 400-1,200 mg daily in divided doses (maximum of 1,600 mg a day). The half-life is approximately 2 hours in the initial phase and 8 hours in the terminal phase. The drug is partially metabolized in the liver and excreted in the feces via bile (McEvoy et al., 2005). Ketoconazole enhances the effect of anticoagulant drugs such as warfarin. Common adverse effects are nausea, dizziness, abdominal pain, diarrhea, headache, pruritus, lethargy, nervousness, somnolence, rash, elevated liver transaminases, and gynecomastia. Serious reactions include adrenal insufficiency, thrombocytopenia, hepatic failure, hepatotoxicity, anaphylaxis, leukopenia, and hemolytic anemia (ePocrates Rx, 2005).
Aminoglutethimide normalizes urinary free cortisol in patients 50% of the time (Greenberg, 2001). Dosing starts at 125-250 mg orally twice a day. Because effectiveness may diminish over time, a dosage increase may be required. However, the total dose should not exceed 1,000 mg per day. Side effects, which are dose dependent, include sedation, anorexia, nausea, rash, and hypothyroidism. When aminoglutethimide is used in combination with irradiation, it is highly effective in most patients (Shimon & Melmed, 1998).
Metyrapone is involved in one of the final steps of cortisol synthesis and may be used alone or in combination with other medications. Daily plasma cortisol is normalized to approximately 75% when patients are treated with metyrapone. (The drug is not FDAapproved for this use.) Dosage is 750-6,000 mg per day in divided doses given three times a day, with meals. Metyrapone has a plasma half-life of about 20-26 minutes, as it is rapidly metabolized in the liver and kidneys (McEvoy et al., 2005). Metyrapone should not be used by patients with adrenocortical insufficiency or by those who are on corticosteroids. The medication's effectiveness may diminish with time. Side effects include lethargy, dizziness, ataxia, nausea, vomiting, primary adrenal insufficiency, hirsutism, and acne (ePocrates Rx, 2005). Overall, aminoglutathemide and metyrapone are more expensive, less effective, and have more side effects than ketoconazole (Arafah & Nasrallah, 2001).
Mitotane inhibits several steps in glucocorticoid synthesis. After 6-12 months of treatment, 75% of patients enter remission. The dosage is 250-500 mg given orally before bed and increased slowly. The usual range is 4-12 g per day in divided doses and is taken three or four times a day. Plasma half-life is 18-159 days with the drug being metabolized in the liver and excreted through urine and bile (McEvoy et al., 2005). Again, initial effectiveness may diminish with time. Side effects include anorexia, lethargy, dizziness, impaired cognition, GI distress, hypercholesterolemia, and adrenal insufficiency (ePocrates Rx, 2005). Mitotane used with pituitary irradiation appears more effective than mitotane or radiation therapy alone (McEvoy et al.).
Cyproheptadine is effective in only a small number of cases. It is a serotonin antagonist and its effectiveness is increased when combined with bromocriptine. The dosage is 8-36 mg per day in divided doses that are administered three times a day. Side effects include sedation and hyperphagia (abnormally increased appetite for food) with weight gain (MedlinePlus, 2005).
Treatment of Growth Hormone-Secreting Adenomas
For patients with growth hormone-secreting adenomas not cured by surgery or with contraindications to surgery, or with tumors that recur after surgery or radiation treatment, pharmacological therapy is indicated. Current medications can include one or more of the following: bromocriptine, cabergoline, pergolide, lisuride, depo-bromocriptine, octreotide, or octreotide plus a dopamine agonist. In addition, an experimental drug called pegvisomant is entering trials. Medication ranges and costs for these treatments are summarized in Table 1.
Bromocriptine lowers GH levels to less than 10 mcg/ml in 54% of cases and to less than 5 mcg/ml in only 12%. Tumor shrinkage occurs in only approximately 20% of patients on bromocriptine (Shimon & Melmed, 1998). Higher doses of bromocriptine are usually required for growth hormone-secreting adenomas than for prolactinomas and should be periodically withdrawn to assess the GH levels. For growth hormone tumors that respond to bromocriptine, the usual dosage is 20-60 mg per day in divided doses with a maximum daily dose of 100 mg.
Octreotide acetate is a synthetic somatostatin analogue that binds to somatostatin receptors or somatotroph tumors and inhibits GH synthesis and secretion. It is 45 times more potent than endogenous somatostatin in suppressing GH secretion (Veznedaroglu, Armonda, & Andrews, 1999). It also has a longer half-life (2 hours after subcutaneous injection) than somatostatin (only minutes), and it does not result in rebound GH hypersection. GH levels are reduced in 71% of those using octreotide, while IGF-1 levels are reduced in 93% (Greenberg, 2001). Normal GH levels are achieved in 50-66% of those taking octreotide, and 66% achieve normal IGR-1 levels (Arafah & Nasrallah, 2001). Tumor volume is reduced significantly in about 30% of cases. Octreotide causes tumor shrinkage with fibrosis and proves helpful in preoperative management (Veznedaroglu et al., 1999). Octreotide is often given in combination with bromocriptine (Greenberg), and many symptoms will improve within the first few weeks. Some patients with acromegaly also have diabetes, and for them, octreotide therapy enhances insulin sensitivity and dramatically decreases insulin requirements (Shimon & Melmed, 1998). Octreotide is twice as potent as the dopamine agonists in suppressing insulin secretion.
After a 50 mcg subcutaneous injection of octreotide, GH secretion is suppressed within 1 hour; the nadir occurs at 3 hours. GH remains reduced for 6-8 hours. Treatment starts with 50-100 mcg subcutaneously every 8 hours, and the dose can be increased up to a maximum of 1,500 mcg per day. Doses greater than 750 mcg per day are rarely needed. The average dose required is 100-200 mcg subcutaneously every 8 hours. Common reactions are diarrhea, abdominal pain, flatulence, biliary tract abnormalities, constipation, nausea and vomiting, hyperglycemia, injection site pain, cholelithiasis, upper respiratory infection symptoms, flu syndrome, fatigue, dizziness, headache, malaise, fever, dyspnea, arthropathy, hypothyroidism, and hypoglycemia. Serious reactions are cholecystitis, ascending cholangitis, bradycardia, arrhythmias, cardiac conduction disturbance, syncope, severe edema, congestive heart failure, and hypertension. Rare and serious reactions include biliary obstruction, cholestatic hepatitis, pancreatitis, and anaphylaxis (ePocrates Rx, 2005).
Sandostatin LAR(R) (octreotide acetate in longeracting form) and lanreotide-SR are long-acting, slow-release somatostatin preparations. Primarily, they suppress secretion of GH and, secondarily, they suppress IGF-1 (somatomedin-C). After repeated intramuscular injections, octreotide concentrations remain at therapeutic values for 4-6 weeks and lead to better patient compliance (Arafah & Nasrallah, 2001). The dosage for Sandostatin LAR is one 20-40 mg intramuscular injection every 30 days, starting at 20 mg and adjusted per GH levels. Lanreotide-SR is given intramuscularly in a fixed dose of 30 mg every 7-21 days (Arafah & Nasrallah). Lanreotide-SR, however, has not been approved by the FDA for growth hormone-secreting tumors (Shimon & Melmed, 1998).
Pegvisomant is a 191 aa recombinant protein (genetically engineered DNA) with two binding sites affecting the production of GH and IGF-1. Pegvisomant is presently being tested in randomized double-blind multicenter trials and is receiving promising results (Arafah & Nasrallah, 2001). Health professionals may see this drug used in the future for treatment of acromegaly.
Summary
Because pituitary adenomas can present in many ways, nurses need to be aware of the signs and symptoms of different hormone-secreting tumors and their related pharmacologic treatment. Although long-term medical management of secreting tumors and their hormonal complications is usually carried out on an outpatient basis, diagnosis often occurs during inpatient care. Consequently, nurses in both settings need to be knowledgeable about medications used, outcomes expected, and adverse effects experienced. Patient care should be centered around education and management of complications as patient compliance is increased with knowledge.
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