Growth Hormone-Secreting Pituitary Tumors

Mary H. Samuels

CHAPTER 21

GROWTH HORMONE-SECRETING PITUITARY TUMORS 1. What is the normal function of growth hormone in children and adults? In children, growth hormone (GH) is responsible for linear growth. In children and adults, GH has many effects on intermediary metabolism, including protein synthesis and nitrogen balance, carbohydrate metabolism, lipolysis, and calcium homeostasis. 2. How are levels of GH normally regulated? Pituitary secretion of GH is regulated by two hypothalamic hormones: stimulatory GH-releasing hormone (GH-RH) and inhibitory somatostatin. Secretion of GH is also affected by adrenergic and dopaminergic hormones, as well as by other central nervous system factors. 3. Does GH directly affect peripheral tissues? No. Many (although not all) effects of GH are mediated by another hormone called somatomedin-C or insulin-like growth factor type 1 (IGF-1). IGF-1 is made by the liver and other organs in response to stimulation by GH. IGF-1 feeds back to the pituitary gland and suppresses GH secretion. Unlike GH, IGF-1 has a long half-life in plasma; thus plasma levels of IGF-1 are helpful in the diagnosis of GH abnormalities. 4. What are the clinical features of excessive production of GH in children? In children who have not yet undergone puberty and whose long bones still respond to GH, excessive GH causes accelerated linear growth. The result is gigantism. 5. Describe the clinical features of excessive production of GH in adults. In adults, excessive GH causes acromegaly. The pathologic and metabolic effects of acromegaly are summarized in Table 21-1. 6. What is the single best clue in examining a patient suspected of having acromegaly? An old driver’s license picture or other old photographs provide the best clues. Patients with acromegaly are often unaware of the gradual disfigurement due to the disease or attribute it to aging. Comparing serial photographs can help to establish the diagnosis, as well as date its onset. 7. From what do patients with acromegaly die? Acromegaly increases cardiovascular and metabolic resk factors, including hypertension, glucose intolerance, cardiomyopathy, and sleep apena. The mortality from untreated or inadequately treated acromegaly is about double the expected rate in healthy subjects matched for age. Major causes of death include hypertension, cardiovascular disease, diabetes, pulmonary infections, and cancer. 8. In patients with acromegaly, are skin tags all over the neck and chest a relevant finding? There appears to be an association between multiple skin tags and colonic polyps in acromegaly. Therefore the patient should undergo careful colonoscopic screening for polyps and colon cancer. However, even patients without active disease or skin tags may be at risk for colonic neoplasia and probably should be screened regularly, according to conventional guidelines.

185

186 CHAPTER 21 GROWTH HORMONE-SECRETING PITUITARY TUMORS TABLE 21-1.

CLINICAL EFFECTS OF ACROMEGALY

Clinical Effect

Cause

Coarse features

Periosteal formation of new bone

Enlarged hands and feet

Soft tissue hypertrophy

Excess sweating

Hypertrophy of sweat glands

Deepened voice

Hypertrophy of larynx

Skin tags

Hypertrophy of skin

Upper airway obstruction and sleep apnea

Hypertrophy of tongue and upper airway

Osteoarthritis

Hypertrophy of joint cartilage and osseous overgrowth

Carpal tunnel syndrome

Hypertrophy of joint cartilage and osseous overgrowth

Hypertension, congestive heart failure

Cardiac hypertrophy

Hypogonadism

Multifactorial

Diabetes mellitus, glucose intolerance

Insulin antagonism, other factors

Colonic polypss

Colonic hypertrophy

9. The husband of the patient with acromegaly complains that he cannot sleep because his wife snores so loudly. Is this complaint relevant? Sleep apnea occurs in up to 80% of patients with acromegaly. It can be due to soft tissue overgrowth of the upper airway or to altered central respiratory control. Sleep apnea may contribute to morbidity and mortality in acromegaly by producing hypoxia and pulmonary hypertension. 10. If I suspect that a patient may have acromegaly, what test should I order? The single best screening test for acromegaly is the plasma level of IGF-1. Because plasma levels of IGF-1 are independent of food intake, samples can be drawn any time of day. In adults, acromegaly is essentially the only condition that causes elevated IGF-1 levels. In children, IGF-1 levels are more difficult to interpret because growing children normally have higher levels than adults. 11. The patient’s IGF-1 level is not elevated, but I still think that she may have acromegaly. What other test should I do? The gold standard test to rule out acromegaly is the measurement of serum GH levels in the fasting state and after glucose suppression. Some patients with acromegaly have extremely elevated fasting levels of GH, and further testing is not necessary. Most patients, however, have GH levels that are only mildly elevated or overlap with levels in healthy subjects. Therefore, the diagnosis is usually made by measuring GH levels after a glucose tolerance test. Healthy subjects suppress GH levels after glucose, whereas patients with acromegaly show no suppression or an increase in GH levels. This test is unreliable in patients with diabetes mellitus. 12. After the biochemical diagnosis of acromegaly or gigantism is made, what is the next step? Excessive secretion of GH is almost always due to a benign pituitary tumor. Therefore the next step is to obtain a radiologic study of the pituitary gland. The optimal study is magnetic resonance imaging (MRI) with special cuts through the pituitary gland. If MRI is not available, the best alternative study is a computed tomography (CT) scan with special cuts through the pituitary gland.

CHAPTER 21 GROWTH HORMONE-SECRETING PITUITARY TUMORS 187 13. What causes GH-secreting pituitary tumors? GH-secreting pituitary tumors have been shown to be monoclonal, suggesting that a spontaneous somatic mutation is a key event in neoplastic transformation of somatotrophs. Further studies have clarified the nature of the mutation in some GH tumors that appear to have an altered stimulatory subunit (GS) of the G-proteins that regulate adenylate cyclase activity. In a mutated cell, alterations in the GS subunit cause autonomous adenylate cyclase activity and elevated secretion of GH. However, the mutant GS is found only in a subset of patients with acromegaly. The mechanism of GH regulation and tumor growth may differ in other patients with acromegaly. 14. Are other endocrine syndromes possible in patients with acromegaly or gigantism? Yes. Otherwise acromegaly and gigantism would not be endocrine disorders. Three endocrine syndromes include acromegaly (Table 21-2).

TABLE 21-2.

ENDOCRINE SYNDROMES ASSOCIATED WITH ACROMEGALY Major Involved

Syndrome

Organs

Multiple endocrine neoplasia type 1

Pituitary tumors

(MEN 1)

Parathyroid hyperplasia Islet-cell tumors

Hypercalcemia (most) Peptic ulcer disease (if gastrinoma) Hypoglycemia (if insulinoma)

Check calcium levels in patients with acromegaly

McCune-Albright syndrome

Bones

Polyostotic fibrous dysplasia Cafe´-au-lait spots Sexual precocity

Mostly in girls

Cardiac myomas Pigmented skin lesions Pigmented nodular adrenal hyperplasia Many other tumors

Autosomal dominant

Skin Gonads Others Carney’s complex

Heart Skin Adrenals Others

Clinical Findings

Other Clues Autosomal dominant

15. Do other tumors besides pituitary tumors make GH and cause acromegaly or gigantism? Yes. Rare tumors of the pancreas, lung, ovary, and breast may produce GH. However, only one patient has been reported to develop clinical acromegaly from ectopic GH production (from a pancreatic tumor). 16. Do tumors ever cause acromegaly or gigantism by making excessive GH-RH? Yes. More than 50 cases of GH-RH production by various tumors have been described. These tumors occur in the lung, gastrointestinal tract, or adrenal glands and cause acromegaly by stimulating pituitary secretion of GH. The clinical and biochemical features of acromegaly in such patients are indistinguishable from those of acromegaly due to a pituitary adenoma. Pituitary enlargement also occurs as a result of hyperplasia of somatotrophs. Some patients have had inadvertent transsphenoidal surgery before the correct diagnosis was made. Therefore the plasma level of GH-RH should be measured in any acromegalic patient with an extrapituitary abnormality or with hyperplasia on pituitary pathology.

188 CHAPTER 21 GROWTH HORMONE-SECRETING PITUITARY TUMORS 17. If MRI of the pituitary confirms a tumor in the acromegalic patient, what issues other than the metabolic effects of excessive GH should be considered? 1. Is the tumor making any other pituitary hormones besides GH? For example, many GH-secreting tumors also produce prolactin; rare tumors also make thyroid-stimulating hormone or other pituitary hormones. In patients with acromegaly, prolactin levels should be measured, as well as other hormones when clinically indicated. 2. Is the tumor interfering with the normal function of the pituitary gland? Specifically, what are the patient’s thyroid, adrenal, and gonadal function? Does the patient have diabetes insipidus? It is important to diagnose and treat pituitary insufficiency before therapy for the excessive secretion of GH, especially if the patient is scheduled for surgery. 3. Is the tumor causing effects owing to its size and location? Possible effects include headache, visual field disturbances, and extraocular movement abnormalities. Formal visual fields examination should be carried out in patients with large pituitary tumors. 18. How big are GH-secreting pituitary tumors? GH-secreting tumors vary considerably in size, but most are larger than 1 cm in diameter when diagnosed (i.e., macroadenomas), and some can be very large. Tumor size is an important issue because it determines success rates of treatment.

KEY POINTS: ACROM EGALY 1. Acromegaly leads to gradual soft tissue enlargement and disfigurement over many years, and the patient may be unaware of the changes. 2. Acromegaly causes damage to bones, joints, the heart, and other organs and is associated with considerable morbidity and excess mortality. 3. The best screening test for acromegaly is an insulin-like growth factor type 1 level. 4. The best initial treatment for acromegaly is usually surgery, performed by an experienced pituitary surgeon. 5. There are new medical treatments for acromegaly that are effective in controlling the metabolic effects of excess growth hormone secretion.

19. How should acromegaly or gigantism be treated? The treatment of choice for GH-secreting tumors is transsphenoidal surgery by an experienced neurosurgeon. Most patients with microadenomas are cured, and larger tumors are debulked. Significant reduction in GH levels and improvement in symptoms typically follow surgery, even when further treatment is required. Certain patients may benefit from medical therapy with a somatostating analog before surgery to reduce surgical risks, including patients with congestive heart failure, severe sleep apnea, intubation problems, or other comorbidites of acromegaly. There are no conclusive data that presurgical treatment improves cure rates, however. Primary medical therapy with a somatostatin analog can be considered for carefully selected patients, such as those who are poor surgical candidates or who decline surgery. 20. What if surgery does not cure the patient? Should I recommend radiation therapy? Conventional radiation therapy of GH-secreting tumors causes a gradual decline in GH levels over many years and is not recommended as sole therapy. Stereotactic ‘‘radiosurgery’’ has been applied to pituitary tumors, including acromegaly. Stereotactic radiosurgery consists of applying a highly concentrated high-energy radiation therapy beam to the tumor, and it appears to be

CHAPTER 21 GROWTH HORMONE-SECRETING PITUITARY TUMORS 189 more effective and to work more quickly than conventional radiation therapy for pituitary tumors. However, stereotactic radiosurgery still takes months to years to work. Therefore although it is not a good initial choice, radiation therapy is sometimes used after surgery for additional control of the residual tumor mass, or if medical therapy fails to control the metabolic effects of growth hormone excess. Many patients eventually develop hypopituitarism from radiation therapy. 21. Are there any options for medical therapy of acromegaly? Two agents are effective: octreotide and pegvisomant. 22. Discuss the mechanisms of action of octreotide. Most GH-secreting tumors have somatostatin receptors and respond to exogenous somatostatin with decreases in GH levels. The development of octreotide, a long-acting analog of somatostatin, was a major advance in the treatment of acromegaly. 23. How effective is octreotide? Given as injections two or three times a day, octreotide leads to markedly decreased levels of GH in most acromegalic patients, with amelioration of many of the symptoms and side effects of acromegay. It also causes tumor shrinkage in some patients. However, it does not cure acromegaly; stopping the drug usually leads to increases in GH levels and tumor regrowth. Therefore octreotide must be given indefinitely or while waiting for radiation to take effect. Recently, long-acting depo forms of octreotide have been developed. Now most patients can be treated with an injection once a month rather than two to three times a day. 24. Describe the mechanism of action of pegvisomant. When is it used? Pegvisomant, the newest therapeutic option for acromegaly, blocks GH action at peripheral receptors, improving IGF-1 levels, reducing clinical effects, and correcting metabolic defects. It does not appear to affect tumor size in the great majority of patients, but tumor size should be monitored, given the drug’s mechanism of action. It is currently used for patients who are resistant to or do not tolerate octreotide. 25. What are the side effects of octreotide and pegvisomant? Gastrointestinal side effects are common with octreotide, including abdominal bloating, mild diarrhea, nausea, and flatulence. The incidence of gallstones may be increased with octreotide, and therefore patients should be monitored with serial ultrasonography of the gallbladder. Pegvisomant appears to have few adverse effects, aside from rare elevations in liver function tests. 26. How can one tell whether a patient has been cured of acromegaly? The criteria for cure of acromegaly are somewhat controversial. Older studies defined cure as a random GH level below 5 ng/mL. More recent studies have shown that this criterion is inadequate because patients with low levels of GH may still have acromegaly. Therefore more rigorous criteria have been developed depending on specific GH assays. For complete control of growth hormone secretion, it has recently been recommended that patients should have a normal IGF-1 level and GH levels less than 0.4 ng/mL following oral glucose. 27. The patient has undergone transsphenoidal surgery for acromegaly and now has normal postoperative fasting levels of GH, suppressed levels of GH following oral glucose, and a normal level of IGF-1. How should the patient be followed? It appears that the patient is cured, but GH tumors can slowly regrow over years. At the least, measurements of GH, IGF-1, or both should be repeated every 6 to 12 months. Some physicians

190 CHAPTER 21 GROWTH HORMONE-SECRETING PITUITARY TUMORS also repeat a pituitary MRI at yearly intervals. The patient also requires monitoring for colonic neoplasia at regular intervals. In addition, one must assess whether the surgery damaged normal pituitary function by determining the patient’s thyroid, adrenal, gonadal, and posterior pituitary function. Finally, the effects of surgery on visual fields should be assessed, especially if the patient had preoperative defects. 28. The patient asks which symptoms and physical abnormalities will improve after cure is confirmed. What is the appropriate answer? Most soft tissue changes improve, including coarsening of facial features, increased size of hands and feet, upper airway hypertrophy, carpal tunnel syndrome, osteoarthritis, and excessive sweating. Hypertension, cardiovascular disease, and diabetes also improve. Unfortunately, bony overgrowth of the facial bones does not regress after treatment. 29. For bonus points, name an actor with acromegaly and the movie in which he starred. Andre the Giant starred in The Princess Bride.

BIBLIOGRAPHY 1. Ben-Shlomo A, Melmed S: Acromegaly. Endocrinol Metab Clin North Am 30:565–583, 2001. 2. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25:102–152, 2004. 3. Consensus statement: biochemical assessment and long-term monitoring in patients with acromegaly. Statement from a join consenses conference of the Growth Hormone Research Society and the Pituitary Society. J Clin Endocrinol Metab 89:3099–3102, 2004. 4. Freda PU: Somatostatin analogs in acromegaly. J Clin Endocrinol Metab 87:3013–3018, 2002. 5. Melmed, S, Casanueva F, Cavagnini F, et al: Consensus statement: medical management of acromegaly. Eur J Endocrinol 153:737–740, 2005. 6. Muller AF, Kopchick JJ, Flyvbjerg A, van der Lely AJ: Growth hormone receptor antagonists. J Clin Endocrinol Metab 89:1503–1511, 2004.