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CHAPTER 21 MEDICAL TREATMENT OF PITUITARY TUMORS AND HYPERSECRETORY STATES

CHAPTER 21 MEDICAL TREATMENT OF PITUITARY TUMORS AND HYPERSECRETORY STATES
Principles and Practice of Endocrinology and Metabolism

CHAPTER 21 MEDICAL TREATMENT OF PITUITARY TUMORS AND HYPERSECRETORY STATES

DAVID H. SARNE

Prolactin Hypersecretion

Microprolactinomas

Macroprolactinomas

Idiopathic Hyperprolactinemia

Prolactin Hypersecretion Associated with Other Lesions

Details of Bromocriptine Therapy

Therapy with Other Dopaminergic Agonists
Adrenocorticotropic Hormone Hypersecretion

Centrally Acting Drugs

Peripherally Acting Drugs
Growth Hormone Hypersecretion

Bromocriptine

Somatostatin Analogs

Estrogen Therapy
Gonadotropin Hypersecretion

Gonadotropin-Secreting Adenomas

True Precocious Puberty
Hypersecretion of Thyroid-Stimulating Hormone

Thyroid-Stimulating Hormone–Secreting Adenoma

Isolated Pituitary Resistance to Thyroid Hormone

Nonsecretory Adenomas
Chapter References

PROLACTIN HYPERSECRETION
MICROPROLACTINOMAS
In women with microprolactinomas (tumor diameter of <10 mm) who require therapy for menstrual irregularities, infertility, or galactorrhea, bromocriptine is the treatment of choice.1,2 and 3 A dose of 2.5 to 10 mg per day relieves the symptoms and normalizes serum prolactin in nearly 90% of patients. Approximately 10% of these patients fail to respond to bromocriptine regardless of the dosage, but many treatment failures are related to an inability to tolerate a sufficient dosage. With treatment, prolactin levels may normalize within a few days to several months. A reduction in microadenoma size has been reported in up to 75% of treated patients.
When bromocriptine is discontinued after 1 to 2 years, 20% of patients maintain normal prolactin levels.4 In most patients, hyperprolactinemia recurs, although 25% have prolactin levels less than half the pretreatment value. No test predicts which patients will have sustained normalization. Prolactin levels usually reach a stable plateau within 2 months, but serum prolactin can reach the pretreatment level in <2 weeks. Some authors recommend that bromocriptine therapy be discontinued in patients with prolactin-secreting microadenomas after 1 to 2 years, with reinstitution of therapy only in those patients who again develop elevated levels.
The surgical treatment of microadenomas yields a high initial cure rate (85%), but the procedure is associated with complications. Moreover, with longer follow-up periods, half of these “cured” patients have a recurrence of hyperprolactinemia5 (see Chap. 13 and Chap. 23. Surgical treatment should be reserved for patients whose microadenomas fail to respond to bromocriptine or other dopaminergic agents or for those who are unable to tolerate the side effects of the drug regimen. Because studies of untreated patients have revealed that many microadenomas remain small for years, withholding treatment in patients with asymptomatic hyperprolactinemia may be reasonable.6,7 Nevertheless, although patients may not be disturbed by amenorrhea or galactorrhea, prolonged hypogonadism increases the loss of skeletal mass, so bromocriptine therapy is recommended for these patients, although for women not interested in fertility, estrogen therapy is also an option.3,8
MACROPROLACTINOMAS
The treatment of macroprolactinomas (tumor diameter of ³10 mm) remains controversial. If the goal is to achieve lasting normalization of prolactin after discontinuing therapy, then surgery or radiation therapy is most effective; however, bromocriptine controls prolactin levels in more patients than does either surgery or radiation.9
A treatment regimen of 5 to 15 mg per day of bromocriptine causes serum prolactin levels to fall to <10% of the pretreatment value in 90% of patients and normalizes prolactin levels in ~66% of patients.10 This decline in serum prolactin is usually accompanied by cessation of galactorrhea, return of normal menses in women, and improvement of libido in men. (The resolution of impotence in men occurs less frequently.) The maximal reduction of prolactin usually is seen after 2 to 3 months of therapy; however, some patients require up to 9 months of therapy for maximal suppression of prolactin. The gonadotropin abnormalities frequently found in these patients commonly improve with bromocriptine therapy.11 Abnormal secretion of growth hormone, adrenocorticotropic hormone (ACTH), or thyroid-stimulating hormone (TSH) occurs less frequently than gonadotropin abnormalities but is less likely to resolve.
A reduction in tumor size is seen in 90% of treated patients; most exhibit a size reduction equal to or exceeding 50%.10,12 The extent of the reduction cannot be predicted by either basal or treatment prolactin levels. Prolactin levels usually decline before a reduction in tumor size is noted. In some patients, despite an almost total disappearance of the lesion, serum prolactin levels remain mildly elevated. A significant reduction in tumor size may occur within 6 weeks, but such a reduction may not be evident for at least 6 months, and the process may continue for up to 1 year. In the absence of progressive tumor growth, bromocriptine should be administered for at least 6 months to 1 year before one concludes that it is ineffective. Usually, prolactin levels remain elevated if treatment with bromocriptine does not reduce the tumor’s size. Rarely, the adenoma increases in size despite the suppression of serum prolactin levels.13 When therapy is discontinued, hyperprolactinemia and an increase in tumor size usually follow.14 Reexpansion of the adenoma can be rapid and dramatic. Therefore, treatment withdrawal should be undertaken cautiously and cannot be recommended routinely. If discontinuation of therapy is not accompanied by an increase in serum prolactin levels or by tumor regrowth, necrosis of the adenoma has probably occurred.
The role of bromocriptine in preparing patients for primary surgical treatment remains controversial.15 Bromocriptine therapy should not be discontinued before surgery because rapid tumor reexpansion may result. In patients who are to undergo irradiation, treatment with bromocriptine for 1 to 2 years until the therapy is fully effective is associated with a more rapid improvement in hyperprolactinemia, amelioration of symptoms, and reduction in tumor growth. Bromocriptine is the treatment of choice in patients in whom both surgery and radiation therapy have failed.
IDIOPATHIC HYPERPROLACTINEMIA
When treatment of idiopathic hyperprolactinemia is indicated, bromocriptine is the preferred mode of therapy.16 A treatment regimen of 2.5 to 7.5 mg per day of bromocriptine restores normal prolactin levels, corrects gonadotropin dysfunction, and relieves symptoms in >90% of patients. Surgery and radiation therapy are not indicated for this condition.
PROLACTIN HYPERSECRETION ASSOCIATED WITH OTHER LESIONS
Non–prolactin-secreting adenomas and other central nervous system lesions may increase prolactin levels by interfering with normal hypothalamic inhibition. Bromocriptine, 2.5 to 7.5 mg per day, usually normalizes serum prolactin levels in these patients. The normalization of prolactin is usually associated with the resolution of galactorrhea. Amenorrhea and infertility may also resolve with this mode of therapy; however, when the underlying lesion has disrupted the normal hypothalamic pituitary axis or has destroyed the gonadotropes, use of bromocriptine does not restore menses or fertility.
DETAILS OF BROMOCRIPTINE THERAPY
Bromocriptine (2-Br-a-ergocryptine mesylate) is a semisynthetic ergot alkaloid. It specifically binds to and stimulates dopamine receptors.
One-third of an oral dose is absorbed, and peak serum levels are reached 1 to 3 hours after oral administration. It is extensively metabolized by the liver, with the metabolites being excreted almost entirely by biliary secretion.17 Less than 5% of the drug is excreted in the urine. Maximal suppression of prolactin occurs 6 to 8 hours after a single dose, and suppression may be maintained for 12 to 14 hours.
Treatment with bromocriptine should be initiated with a dose of one-half of a 2.5-mg tablet taken with food just before bedtime, followed by a regimen of 1.25 mg given with food every 8 to 12 hours. Less than 1% of treated patients experience a first-dose phenomenon, characterized by marked faintness or dizziness. This is observed most commonly in elderly patients and in those with a previous history of fainting, peripheral vascular disease, or use of vasodilators. Increases in dosage should be gradual, no more than 2.5 to 5 mg within a period of a few days to 1 week. The total daily dose is usually divided and administered every 8 to 12 hours.
Side effects are usually dose related, with a rapid development of tolerance. Many side effects are potentiated by alcohol, the use of which should be avoided in sensitive patients. To tolerate bromocriptine therapy, some patients may need to begin with a dosage of 0.625 mg per day (one-fourth tablet), thereafter increasing the dosage at 1-week intervals.
Nausea is the most common side effect and occurs in up to 25% of treated patients. The nausea is usually mild, may be minimized by administration of the drug with food and by the initial use of low doses, and generally improves with time.18 Constipation is also frequently reported, and some patients experience abdominal cramps. Seven patients receiving high doses of bromocriptine for the treatment of acromegaly were reported to have had major gastrointestinal hemorrhage associated with peptic ulcer disease (three of these episodes were fatal).18 However, bromocriptine has not been associated with an increased incidence of peptic ulcer disease.
A slight decline in blood pressure is commonly observed in treated patients; however, patients usually remain asymptomatic. Mild orthostatic hypotension has also been noted.18 The decrease in blood pressure is probably related to both a relaxation of vascular smooth muscle and central inhibition of sympathetic tone. As with the gastrointestinal side effects, symptomatic hypotension usually improves with time.
Vascular side effects, including digital vasospasm, livedo reticularis, and erythromelalgia, occur infrequently and are usually associated with bromocriptine doses that exceed those used in the treatment of hyperprolactinemia. Significant mental changes, including hallucinations, have been noted, most commonly in elderly patients receiving large doses of bromocriptine. In two patients, a dose of 5 to 7.5 mg of bromocriptine, administered for treatment of hyperprolactinemia, was reported to have caused psychotic delusions. However, one of these patients had a known history of schizophrenia in remission, and the other was under severe emotional stress. Other side effects of bromocriptine include nasal stuffiness, headache, and fatigue.
Women taking bromocriptine should be advised to use mechanical contraception and, if pregnancy is desired or suspected, to discontinue bromocriptine whenever expected menses are >2 days late. Visual fields should be evaluated regularly during pregnancy. If evidence of tumor enlargement is found, a choice is made between continued observation, treatment with bromocriptine, or transsphenoidal surgery, depending on the status of the individual patient. In the United States, women are usually advised to discontinue bromocriptine therapy during pregnancy; in Europe, however, treatment is commonly continued. A review of 1410 pregnancies in 1335 women who received bromocriptine while pregnant revealed that the incidence of spontaneous abortions (11.1%) and congenital anomalies (3.5%) was no higher than that seen in the general population.19 In women not taking other fertility agents, a slightly increased incidence of twin pregnancies (1.8%) was seen. A retrospective study of 64 children born to 53 mothers who took bromocriptine while pregnant revealed no evidence of adverse effects on motor or psychological development.20
THERAPY WITH OTHER DOPAMINERGIC AGONISTS
Several other dopamine agonists have been developed that may be useful in the treatment of hyperprolactinemia. A parenteral formulation of long-acting bromocriptine has been effective, with intramuscular injections given every 4 weeks. Pergolide is an ergoline derivative that can be given once daily in a dose of 50 to 100 µg.21 Although it is similar to bromocriptine in its effectiveness and side effects, some patients who do not tolerate bromocriptine may tolerate pergolide.22 The nonergot dopamine agonist quinagolide (CV 205-502) can be administered in dosages of 0.1 to 0.5 mg per day, with fewer side effects than bromocriptine or pergolide. Quinagolide was effective in patients who were unable to tolerate bromocriptine and in some patients who failed to respond adequately to bromocriptine.23 Cabergoline is a long-acting ergoline derivative that can be effective when given weekly or biweekly in doses of 0.5 to 2.0 mg. Its efficacy and side effects profile are similar to or better than those of bromocriptine.24 In several studies, tumor shrinkage and normalization of prolactin levels have occurred in patients who could not tolerate bromocriptine or failed to respond adequately.25,26 and 27
ADRENOCORTICOTROPIC HORMONE HYPERSECRETION
When Cushing syndrome is caused by a pituitary tumor (Cushing disease), transsphenoidal surgery is the treatment of choice.3,28 Radiation therapy, by comparison, is less often successful and may take 1 to 2 years to be effective3 (see Chap. 22). Drug treatment is generally not used as a primary mode of therapy except in patients who refuse surgery or irradiation. However, drug treatment may be appropriate in severely ill patients with marked hypokalemia, psychiatric disturbances, infection, or poor wound healing or in patients awaiting transsphenoidal surgery. Medical therapy is also useful in reducing cortisol levels and ameliorating symptoms until pituitary irradiation is fully effective. Finally, drug therapy may be useful in patients in whom surgery and radiation therapy have failed.
Patients with Cushing disease who are treated by adrenalectomy may develop large, ACTH-secreting, pituitary macroadenomas (Nelson syndrome). The response of such lesions to both surgery and irradiation has been disappointing.
Agents used in the treatment of ACTH hypersecretion can be divided into two classes—those that act centrally to reduce ACTH release and those that act peripherally to reduce cortisol production or block its effect (Table 21-1; see Chap. 1). Centrally acting agents are preferred if a drug is to be used for primary therapy; moreover, they are the only agents appropriate for the treatment of Nelson syndrome. Peripherally acting drugs are the preferred agents for rapid preoperative treatment of severely ill patients awaiting surgery. When the treatment regimen involves the chronic use of peripherally acting drugs, the resultant reduction in cortisol and in negative feedback may be followed by an increase in ACTH hypersecretion, thereby necessitating increased dosages of the drug.

TABLE 21-1. Treatment of Adrenocorticotropic Hormone Hypersecretion

CENTRALLY ACTING DRUGS
BROMOCRIPTINE
Unlike the excellent results achieved with bromocriptine therapy in patients with hyperprolactinemia, long-term administration of the drug, even at dosages of 20 to 30 mg per day, effectively reduces ACTH hypersecretion in only a few patients.29 Although a single 2.5-mg dose of bromocriptine reduces ACTH levels in ~40% of patients, many of these short-term responders fail to improve significantly with long-term treatment. Conversely, some patients who fail to respond to a single dose of bromocriptine demonstrate marked improvement in symptoms and in ACTH hypersecretion with prolonged therapy.30 Neither the pretreatment ACTH and cortisol levels nor the tumor size can be used to predict accurately the response to therapy.
CYPROHEPTADINE
The antiserotoninergic effect of cyproheptadine hydrochloride is thought to be the mechanism whereby ACTH secretion is reduced; however, this drug also has anticholinergic, antihistaminic, and antidopaminergic effects. Thirty percent to 50% of patients with Cushing disease achieve an initial clinical remission with this agent.31 Usually, when the drug is discontinued, elevated cortisol levels and symptomatic disease promptly return. No clinical features can predict which patients will respond to cyproheptadine. Importantly, many authors report poor efficacy and significant side effects with this drug. Occasionally, patients with Nelson syndrome have been reported to improve with administration of cyproheptadine.
VALPROIC ACID
The anticonvulsant agent valproic acid (and its derivatives) is a g-aminobutyric acid transaminase inhibitor that decreases ACTH hypersecretion in some patients with Cushing disease or Nelson syndrome. Reduction of tumor size with valproate sodium has been reported in a single instance.32
The drug is highly protein bound and has a serum half-life of 6 to 16 hours. Capsules should be swallowed whole and not chewed to avoid local irritation to the mouth and pharynx. Nausea and vomiting are commonly experienced at the time therapy is initiated. Tolerance to these side effects develops rapidly, and symptoms may be reduced by administering the drug with meals. Fatal hepatic failure has occurred in several patients receiving this drug as an anticonvulsant agent. Liver function tests should be performed before the initiation of therapy and at regular intervals during the first year. The drug should not be used in patients with a history of liver disease and should be discontinued if evidence of hepatic dysfunction is found. However, hepatic dysfunction has been known to progress even after discontinuation of the drug. An increased incidence of neural tube defects has been reported in children whose mothers received this agent during the first trimester of pregnancy.
PERIPHERALLY ACTING DRUGS
METYRAPONE
Metyrapone reduces the production of cortisol by inhibiting 11-b-hydroxylation in the adrenal gland. The dosage is titrated to maintain normal serum cortisol levels (which should be evaluated at multiple intervals throughout the day) or titrated to keep the 24-hour urine free cortisol level within the physiologic range. The maintenance dosage varies from 250 mg three times a day to 1000 mg four times a day.30,33 The metabolism of metyrapone is accelerated by administration of phenytoin (Dilantin).
The most common side effect is gastrointestinal irritation, which can be avoided by administering the drug with food. Despite improvement in serum cortisol levels, some women note worsening of hirsutism and acne during therapy.33 Cost and side effects may be reduced and efficacy enhanced by combining metyrapone with aminoglutethimide, with 1 g per day of each administered in divided doses. Although the manufacture of metyrapone tablets has been discontinued, capsules remain available from the manufacturer.
MITOTANE
Mitotane (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]-ethane or o,p’-DDD) suppresses the function of the zona fasciculata and zona reticularis of the adrenal cortex. The drug has been known to cause necrosis of the adrenal gland, producing acute adrenal insufficiency. Mitotane is inappropriate for rapid treatment because control of cortisol secretion requires 2 to 4 months of therapy.34 It may be useful in the treatment of patients awaiting the full effect of radiation therapy or in those in whom surgery and irradiation have failed.3,30
AMINOGLUTETHIMIDE
Aminoglutethimide reduces cortisol production by inhibiting the conversion of cholesterol to D5-pregnenolone. During short-term therapy, serum cortisol levels usually are suppressed to less than one-half of pretreatment values. In some patients, glucocorticoid insufficiency occurs, necessitating concurrent glucocorticoid replacement therapy. When aminoglutethimide is used to treat patients with Cushing disease, a secondary increase in ACTH levels frequently leads to escape from acceptable control.30 Few patients have been treated for >3 months. Therapy is begun with administration of one 250-mg tablet every 6 hours. This dosage is then increased by 250 mg per day every 1 to 2 weeks until a total daily dose of 2 g is reached.
Significant side effects occur in two-thirds of patients treated with this agent. The most frequent effects of the drug include drowsiness, which occurs in 33% of patients; skin rashes, which affect 16%; and nausea and vomiting, which occur in 13%. Other significant side effects include vertigo and depression. In general, side effects decrease with smaller doses and often improve or disappear after 1 to 2 weeks of continued therapy. Skin rashes may represent allergic or hypersensitivity reactions; if these are severe or persistent, the drug should be discontinued. Interference with thyroid hormone synthesis may produce hypothyroidism. Decreased estrogen synthesis may produce menstrual irregularities and increased hirsutism and acne in some women. Two cases of pseudohermaphroditism were reported in female infants of mothers who took this drug while pregnant.
Because aminoglutethimide increases dexamethasone metabolism, hydrocortisone or cortisone acetate is preferred if glucocorticoid replacement therapy is needed. Inhibition of aldosterone synthesis may produce mineralocorticoid deficiency, presenting with orthostatic or persistent hypotension, which may require therapy with fludrocortisone acetate (Florinef).
TRILOSTANE
Trilostane is an inhibitor of the 3-b-hydroxysteroid dehydrogenase: D4,D5-isomerase enzyme system. It is generally less effective than the agents described earlier, and results are highly variable.35 Therapy is initiated with 30 mg of trilostane four times a day. This dosage is then increased as required to control serum cortisol and urinary cortisol levels, with an increase every 3 to 4 days until a total dose of 480 mg per day is reached. Significant side effects occur in half of treated patients. Gastrointestinal symptoms are the most common of these, with abdominal pain and discomfort being reported in 16% of patients, diarrhea in 17%, and nausea and vomiting in 5%. Trilostane has been reported to decrease progesterone levels, which has led to cervical dilation and termination of pregnancy in some women.
KETOCONAZOLE
Ketoconazole is an antimycotic agent that decreases serum cortisol by inhibiting cholesterol synthesis through blockade of the 14-demethylation of lanosterol. Ketoconazole may also inhibit 11-hydroxylation and may decrease the binding of glucocorticoid to its receptor. This drug has been reported to be effective in the treatment of patients with Cushing disease in whom surgery and other drug therapy have proved unsuccessful.3,30,36
After oral administration, the drug is rapidly absorbed. An acid pH is required for absorption; therefore, in patients who are also taking antacids or antihistaminic H2-inhibitors, the drug should be administered 2 hours after such therapy. Patients with achlorhydria may need to dissolve the tablets in aqueous hydrochloric acid. In serum, the drug is 99% protein bound.
In patients with Cushing disease, therapy is initiated with 400 mg of ketoconazole administered every 12 hours for 1 month; this dosage is then decreased to 400 to 600 mg per day. Urinary cortisol levels were reported to decline significantly within 1 day after onset of therapy. In patients receiving conventional antifungal doses (200–400 mg per day), the most common side effects are nausea and vomiting, occurring in 3%, and abdominal pain, occurring in 1.5%. Hepatotoxicity has been reported to occur in 1 in 10,000 treated patients; this condition usually resolves on discontinuation of the drug. However, one fatal case of hepatic necrosis that progressed despite discontinuation of the drug was reported.
GLUCOCORTICOID RECEPTOR ANTAGONIST
Mifepristone (RU 486) is a synthetic steroid agonist antagonist that blocks the binding of glucocorticoids to their receptor. It is under investigation as a potential therapeutic agent in the treatment of Cushing disease.37
GROWTH HORMONE HYPERSECRETION
Transsphenoidal surgery remains the treatment of choice for growth hormone–secreting adenomas (see Chap. 23). The overall rate of cure (defined as serum growth hormone levels of <5 ng/mL) is ~68% (88% of microadenomas and 59% of macroadenomas).38 Approximately 75% of patients who undergo conventional radiation therapy eventually achieve normalization of serum growth hormone levels over several years (see Chap. 22). The cure rate with proton beam irradiation of tumors without extrasellar extension approaches 95%. Medical therapy has generally been reserved for those patients who refuse surgery or radiation therapy or in whom these treatment modalities have been unsuccessful as well as for those patients awaiting the full effects of irradiation. Pretreatment with somatostatin analogs may improve surgical outcomes.39 In patients with acromegaly secondary to paraneoplastic (“ectopic”) growth hormone–releasing hormone secretion (see Chap. 12 and Chap. 219), removal of the tumor secreting growth hormone–releasing hormone is the treatment of choice. If this is impossible, medical treatment may be indicated.
BROMOCRIPTINE
Bromocriptine, at a dosage of 20 to 60 mg per day, is effective in many patients with acromegaly. At this dosage level, growth hormone levels are suppressed by more than half in ~70% of patients, but normalization is observed in <25%.40,41 Symptomatic improvement (decreased sweating, decreased softtissue swelling, improvement of sexual functioning, and decreased joint swelling) and an improvement in glucose tolerance are noted in 80% to 90% of patients.40,41 This discrepancy between growth hormone reduction and clinical improvement has been attributed to changes in the form of growth hormone secreted. Most authors recommend the use of insulin-like growth factor-I (IGF-I; also known as somatomedin C), rather than multiple determinations of growth hormone levels, to monitor therapy. In a few patients, a decrease in tumor size was observed. As with hyperprolactinemia, other dopamine agonists also appear to be effective in the treatment of acromegaly.42,43
Bromocriptine maintenance therapy in patients with acromegaly usually requires a minimum of 10 to 20 mg per day; and some patients require up to 80 mg per day. Bromocriptine dosage should be increased slowly to the maximum tolerated dose or until growth hormone levels normalize. Because the drug’s half-life may vary, control may be assessed by measuring growth hormone levels three times the morning after a regular evening dose and then every 2 hours for 8 hours after the patient’s usual morning dose. If serum growth hormone levels have not been suppressed significantly after several months of the maximum tolerated dosage, the drug should be discontinued.
Most patients who respond to long-term bromocriptine therapy exhibit a marked reduction in growth hormone levels within 4 to 8 hours after a single 2.5-mg dose. Patients have been treated for up to 5 years, with maintenance of growth hormone suppression and clinical improvement. Discontinuation of the drug is usually followed by a rapid increase in growth hormone to pretreatment levels and a return of symptoms. Because patients who have undergone previous radiation therapy may have a normal serum growth hormone level years after treatment, bromocriptine use in these patients should be discontinued for 4 to 8 weeks every 1 to 2 years to reevaluate growth hormone secretion.
SOMATOSTATIN ANALOGS
Although somatostatin, a physiologic growth hormone inhibitor, lowers serum growth hormone levels in patients with acromegaly, it requires continuous infusion. In addition, the suppression of insulin secretion leads to hyperglycemia, and rebound growth hormone secretion is often observed after the infusion is discontinued. The longer-acting somatostatin analog octreotide acetate (SMS 201-995; see Chap. 169) is considerably more potent in the suppression of growth hormone. Growth hormone levels are suppressed for 8 to 12 hours after the subcutaneous administration of this analog. Octreotide has become the drug of choice for the medical therapy of acromegaly. It has been used successfully as primary therapy in patients with acromegaly44 as well as in patients in whom surgery and radiation therapy have failed and in whom control has not been achieved with dopaminergic drugs.3,45,46 and 47
Therapy is initiated with 50 µg given subcutaneously every 12 hours, and the dose is increased based on the clinical and biochemical response. Many patients achieve a maximal response with a dosage of 100 µg three times per day, but some may require that octreotide be administered at higher doses or every 6 hours. Some have been treated with up to 500 µg three times per day or by continuous subcutaneous infusion. Symptomatic improvement is noted in 90% of patients within days to weeks. In patients who respond to the drug, growth hormone reductions are apparent after the first dose, and an IGF-I response is noted within 2 weeks. A reduction in growth hormone secretion occurs in 70% of patients, and mean growth hormone levels are usually normalized if the pretreatment value was <20.45,46 IGF-I levels are reduced in 90% of patients and normalized in 60%.45,46 Partial tumor shrinkage has been found in 20% to 50% of patients.45,46 Some patients who do not respond adequately to either octreotide or a potent dopamine agonist have a greater response when the two agents are administered together.
Mild to moderate side effects are noted by one-third of patients, including pain at the injection site, abdominal pain, diarrhea and steatorrhea, vitamin B12 malabsorption, gastritis, and worsening of glucose tolerance (although this also improved in many patients with effective therapy of the acromegaly).45 Of greatest concern has been the development of gallstones, which may occur in up to 18% of patients. Some physicians administered a cholelitholytic agent with octreotide.48 Gallstones resolved after octreotide was discontinued. No rebound increase in growth hormone levels after discontinuation of the drug has been reported.
Sandostatin LAR is a long-acting formulation of octreotide. Intramuscular injections of 20 to 30 mg every 4 weeks have been shown to be effective for up to 3 years in suppressing growth hormone and IGF-I levels and in inducing tumor shrinkage.49,50 As with octreotide, side effects include pain at the injection site, gastrointestinal symptoms, and, infrequently, development of gallstones or B12 malabsorption49,50
Lanreotide is a depot preparation of somatostatin. Intramuscular injections of 30 mg every 10 to 14 days have also been shown to be effective in suppressing growth hormone and IGF-I levels and in inducing tumor shrinkage.51,52 As with the other treatment modalities, symptomatic improvement may be greater than the changes in IGF-I or growth hormone. Side effects are similar to those of octreotide and Sandostatin LAR.52a Further studies are needed to determine which of the two long-acting preparations is more effective.52b
ESTROGEN THERAPY
A decline in IGF-I levels in acromegalic patients treated with estrogen has suggested that this might be a useful therapy. However, estrogen appears to directly suppress IGF-I generation and does not decrease growth hormone or appreciably influence the symptomatology.
GONADOTROPIN HYPERSECRETION
GONADOTROPIN-SECRETING ADENOMAS
The standard therapy for gonadotropin-secreting adenomas is surgical resection, often followed by radiation therapy. However, this approach is rarely curative. Marked reductions (but not normalization) of follicle-stimulating hormone and a-subunit secretion have been seen in patients receiving bromocriptine after unsuccessful surgical therapy or as primary therapy.53 Octreotide therapy has reduced a-subunit secretion and produced tumor shrinkage in a few patients.54 Medical therapy should be considered only for those patients who refuse surgical and radiation therapy or in whom such treatment has failed.
Partial suppression of follicle-stimulating hormone was reported in male patients receiving testosterone or human chorionic gonadotropin (which increases endogenous testosterone).53 Clomiphene citrate or estrogen failed to suppress gonadotropin secretion in these patients, and in one patient, estrogen therapy increased luteinizing hormone and a-subunit secretion.
TRUE PRECOCIOUS PUBERTY
Previously, treatment of true precocious puberty was limited to the use of medroxyprogesterone acetate or cyproterone acetate. These agents failed to arrest bone age advancement adequately and were associated with significant side effects, including adrenal suppression, hypertension, and excessive weight gain. Moreover, they led to reduced fertility and an increased incidence of reproductive tumors in some patients.
Long-acting gonadotropin-releasing hormone agonists are effective in the management of central precocious puberty. These agents include leuprolide, nafarelin, and histrelin.55,56 Although they initially stimulate further hormonal release, their continued use produces a marked suppression of spontaneous and stimulated gonadotropin release. This suppression is accompanied by a reduction in the circulating level of sex steroids (see Chap. 16 and Chap. 225).
Although children treated with these agents continue to grow, a marked reduction in height velocity and a retardation in the advancement of bone age are seen. In some patients, an improvement in predicted attained height occurs. The gain in height is greatest with early initiation of therapy. In girls, a reduction in breast diameter, regression of pubic hair, and a cessation of menses (except for a menstrual period after the initial rapid rise and fall in estrogen level) may be seen.55,56 By ultrasonography, uterine and ovarian size decrease, and ovarian cysts decrease or resolve. In boys, testicular volume is reduced and the frequency of erections and aggressive behavior is markedly decreased.55,56 On discontinuation of therapy, serum gonadotropin and sex steroid levels rapidly return to pretreatment pubertal values, height velocity and bone age increase, and the development of secondary sexual characteristics progresses.55,57
Leuprolide, histrelin, and buserelin are administered as once-daily subcutaneous injections, but nafarelin is administered as a nasal spray; leuprolide is also available in a sustained-release preparation for depot intramuscular injections. Gonadotropin and sex steroid hormone levels are elevated during the first week of therapy but are then significantly reduced as long as therapy is maintained. If the plasma concentrations of sex steroids are not adequately suppressed in multiple samples obtained over several hours (estradiol level of <15 pg/mL in girls and testosterone level of <20 ng/dL in boys), the dosage is increased until adequate suppression is attained. The most common side effect is erythema at the injection site, seen in nearly one-third of treated patients. In two-thirds of these patients, the reaction does not progress. Two patients with erythema and wheal formation were desensitized and were treated with oral diphenhydramine hydrochloride (Benadryl). No patient developed immunoglobulin G antibodies against the analog. One-fourth of the girls treated with these agents developed hot flashes, which in one patient persisted for 2 years.
HYPERSECRETION OF THYROID-STIMULATING HORMONE
THYROID-STIMULATING HORMONE–SECRETING ADENOMA
The rare patients who have TSH-secreting adenoma present with increased serum levels of TSH and symptomatic thyrotoxicosis. They are usually treated surgically58,59 (see Chap. 15 and Chap. 42). Some suppression of TSH has been observed with bromocriptine therapy, but this has been inadequate to normalize thyroid hormone levels; a slight reduction in tumor size was reported in one patient. Conventional antithyroid therapy treats the thyrotoxicosis but not the primary lesion. Trials with octreotide acetate, however, appear promising.47,60
ISOLATED PITUITARY RESISTANCE TO THYROID HORMONE
Patients with isolated pituitary resistance to thyroid hormone also present with TSH hypersecretion and symptomatic thyrotoxicosis, but have no demonstrable tumor. Unlike patients with TSH-secreting adenomas, TSH in these patients is suppressed by thyroid hormone administration.58
Because patients are thyrotoxic, treatment with conventional thyroid hormone is not suitable for long-term management. Treatment with propylthiouracil or methimazole reduces thyroid hormone levels but markedly increases TSH secretion. Bromocriptine therapy has been found to reduce TSH levels in some of these patients; usually, however, the serum TSH level remained elevated, and the patients continued to exhibit signs of mild thyrotoxicosis.61 The combination of propylthiouracil and bromocriptine may produce euthyroidism with only a minimally elevated serum TSH. In one family, the use of 60 µg of triiodothyronine once daily led to TSH suppression, normalization of serum thyroxine, and amelioration of symptoms, but this mode of treatment was unsuccessful in other patients.62 In one patient, the relatively inactive triiodothyronine metabolite triiodothyroacetic acid (TRIAC) was used to normalize TSH and thyroid hormone values.63
NONSECRETORY ADENOMAS
The standard treatment modality for nonsecretory adenomas, if large, is transsphenoidal adenomectomy. However, in a series of 11 patients treated with bromocriptine (15 to 60 mg per day), 9 patients showed an average reduction in tumor size of 38%, whereas 2 patients exhibited a progressive increase in tumor size with treatment.64 Bromocriptine and other dopamine agonists may be useful as adjunctive therapy in patients with nonsecretory lesions or in those who cannot tolerate surgery, but their use cannot be recommended routinely as primary therapy.
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