1.

GROWTH HORMONE-SECRETINGPITUITARY TUMORSMary H. Samuels

CH

APTER21

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, GHhas 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-releasinghormone (GH-RH) and inhibitory somatostatin. Secretion of GH is also affected by adrenergicand 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 calledsomatomedin-C or insulin-like growth factor type 1 (IGF-1). IGF-1 is made by the liver and otherorgans in response to stimulation by GH. IGF-1 feeds back to the pituitary gland and suppressesGH secretion. Unlike GH, IGF-1 has a long half-life in plasma; thus plasma levels of IGF-1 arehelpful 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 acromegalyare summarized in Table 21-1.

6. What is the single best clue in examining a patient suspected of havingacromegaly?

An old driver’s license picture or other old photographs provide the best clues. Patients withacromegaly 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 orinadequately treated acromegaly is about double the expected rate in healthy subjectsmatched 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 arelevant 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 coloncancer. However, even patients without active disease or skin tags may be at risk for colonicneoplasia and probably should be screened regularly, according to conventional guidelines.

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TABLE 21-1. C L I N I C A L E F F E C T S O F A CROMEGA L Y

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 osseousovergrowth

Carpal tunnel syndrome Hypertrophy of joint cartilage and osseousovergrowth

Hypertension, congestive heart failure Cardiac hypertrophy

Hypogonadism Multifactorial

Diabetes mellitus, glucose intolerance Insulin antagonism, other factors

Colonic polypss Colonic hypertrophy

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9. The husband of the patient with acromegaly complains that he cannot sleepbecause 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 tissueovergrowth of the upper airway or to altered central respiratory control. Sleep apnea maycontribute to morbidity and mortality in acromegaly by producing hypoxia and pulmonaryhypertension.

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 ofIGF-1 are independent of food intake, samples can be drawn any timeof day. In adults, acromegaly isessentially the only condition that causes elevated IGF-1 levels. In children, IGF-1 levels are moredifficult 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 haveacromegaly. What other test should I do?

The gold standard test to rule out acromegaly is the measurement of serum GH levels in thefasting state and after glucose suppression. Some patients with acromegaly have extremelyelevated 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. Healthysubjects suppress GH levels after glucose, whereas patients with acromegaly show nosuppression 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 thenext step?

Excessive secretion of GH is almost always due to a benign pituitary tumor. Therefore the nextstep is to obtain a radiologic study of the pituitary gland. The optimal study is magneticresonance 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 thepituitary 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 spontaneoussomatic mutation is a key event in neoplastic transformation of somatotrophs. Further studieshave clarified the nature of the mutation in some GH tumors that appear to have an alteredstimulatory subunit (GS) of the G-proteins that regulate adenylate cyclase activity. In a mutatedcell, alterations in the GS subunit cause autonomous adenylate cyclase activity and elevatedsecretion 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 orgigantism?

Yes. Otherwise acromegaly and gigantism would not be endocrine disorders. Three endocrinesyndromes include acromegaly (Table 21-2).

TABLE 21-2. E N DOCR I N E S YNDROMES AS SOC I A T E D W I T H A CROMEGA L Y

Syndrome

Major Involved

Organs Clinical Findings Other Clues

Multiple endocrineneoplasia type 1

Pituitary tumors Autosomaldominant

(MEN 1) ParathyroidhyperplasiaIslet-cell tumors

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

Check calciumlevels in patientswith acromegaly

McCune-Albrightsyndrome

Bones

SkinGonadsOthers

Polyostotic fibrousdysplasiaCafe-au-lait spotsSexual precocity

Mostly in girls

Carney’s complex HeartSkin

Adrenals

Others

Cardiac myomasPigmented skinlesionsPigmented nodularadrenal hyperplasiaMany other tumors

Autosomaldominant

15. Do other tumors besides pituitary tumors make GH and cause acromegaly orgigantism?

Yes. Rare tumors of the pancreas, lung, ovary, and breast may produce GH. However, only onepatient has been reported to develop clinical acromegaly from ectopic GH production (from apancreatic 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. Thesetumors occur in the lung, gastrointestinal tract, or adrenal glands and cause acromegaly bystimulating pituitary secretion of GH. The clinical and biochemical features of acromegaly insuch patients are indistinguishable from those of acromegaly due to a pituitary adenoma.Pituitary enlargement also occurs as a result of hyperplasia of somatotrophs. Some patientshave had inadvertent transsphenoidal surgery before the correct diagnosis was made. Thereforethe plasma level of GH-RH should be measured in any acromegalic patient with an extrapituitaryabnormality or with hyperplasia on pituitary pathology.

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17. If MRI of the pituitary confirms a tumor in the acromegalic patient, what issuesother 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-stimulatinghormone or other pituitary hormones. In patients with acromegaly, prolactin levels shouldbe measured, as well as other hormones when clinically indicated.

2. Is the tumor interfering with the normal function of the pituitary gland? Specifically, whatare the patient’s thyroid, adrenal, and gonadal function? Does the patient have diabetesinsipidus? It is important to diagnose and treat pituitary insufficiency before therapy forthe 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 includeheadache, visual field disturbances, and extraocular movement abnormalities. Formalvisual 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 whendiagnosed (i.e., macroadenomas), and some can be very large. Tumor size is an important issuebecause it determines success rates of treatment.

KEY POINTS: ACROMEGALY

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 associatedwith 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 experiencedpituitary surgeon.

5. There are new medical treatments for acromegaly that are effective in controlling themetabolic 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 experiencedneurosurgeon. Most patients with microadenomas are cured, and larger tumors are debulked.Significant reduction in GH levels and improvement in symptoms typically follow surgery, evenwhen further treatment is required. Certain patients may benefit from medical therapy with asomatostating analog before surgery to reduce surgical risks, including patients with congestiveheart failure, severe sleep apnea, intubation problems, or other comorbidites of acromegaly.There are no conclusive data that presurgical treatment improves cure rates, however. Primarymedical 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 radiationtherapy?

Conventional radiation therapy of GH-secreting tumors causes a gradual decline in GH levelsover many years and is not recommended as sole therapy. Stereotactic ‘‘radiosurgery’’ has beenapplied to pituitary tumors, including acromegaly. Stereotactic radiosurgery consists of applyinga highly concentrated high-energy radiation therapy beam to the tumor, and it appears to be

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more effective and to work more quickly than conventional radiation therapy for pituitarytumors. However, stereotactic radiosurgery still takes months to years to work. Thereforealthough it is not a good initial choice, radiation therapy is sometimes used after surgery foradditional control of the residual tumor mass, or if medical therapy fails to control the metaboliceffects of growth hormone excess. Many patients eventually develop hypopituitarism fromradiation 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 exogenoussomatostatin with decreases in GH levels. The development of octreotide, a long-acting analogof 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 GHin most acromegalic patients, with amelioration of many of the symptoms and side effects ofacromegay. It also causes tumor shrinkage in some patients. However, it does not cureacromegaly; 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 betreated 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 peripheralreceptors, improving IGF-1 levels, reducing clinical effects, and correcting metabolic defects. Itdoes not appear to affect tumor size in the great majority of patients, but tumor size should bemonitored, given the drug’s mechanism of action. It is currently used for patients who areresistant 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, milddiarrhea, 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 liverfunction 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 arandom GH level below 5 ng/mL. More recent studies have shown that this criterion isinadequate because patients with low levels of GH may still have acromegaly. Therefore morerigorous criteria have been developed depending on specific GH assays. For complete control ofgrowth hormone secretion, it has recently been recommended that patients should have anormal 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 nowhas normal postoperative fasting levels of GH, suppressed levels of GHfollowing oral glucose, and a normal level of IGF-1. How should the patient befollowed?

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

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also repeat a pituitary MRI at yearly intervals. The patient also requires monitoring for colonicneoplasia at regular intervals. In addition, one must assess whether the surgery damagednormal pituitary function by determining the patient’s thyroid, adrenal, gonadal, and posteriorpituitary function. Finally, the effects of surgery on visual fields should be assessed, especially ifthe patient had preoperative defects.

28. The patient asks which symptoms and physical abnormalities will improve aftercure is confirmed. What is the appropriate answer?

Most soft tissue changes improve, including coarsening of facial features, increased size ofhands and feet, upper airway hypertrophy, carpal tunnel syndrome, osteoarthritis, and excessivesweating. Hypertension, cardiovascular disease, and diabetes also improve. Unfortunately, bonyovergrowth of the facial bones does not regress after treatment.

29. For bonus points, name an actor with acromegaly and the movie in which hestarred.

Andre the Giant starred in The Princess Bride.

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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 PituitarySociety. 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. EurJ Endocrinol 153:737–740, 2005.

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