Acromegaly

Acromegaly is an uncommon but fascinating clinical syndrome. While much has been learned about the pathogenesis, hormonal features and treatment of this condition, the diagnosis is still based on careful clinical observation and a systematic laboratory and radiologic evaluation.

Illustrative Case

CASE 1

A 49-year-old man with Gilbert's disease and cholelithiasis presented for a periodic physical examination. He had recently been evaluated by a dentist because of increased interdental spaces. He reported enlargement of his hands, deepening of his voice and increases in shoe size and shirt-sleeve length. He was not taking any medications, and he had no other significant medical history. Figure 1 shows the patient at a younger age and at the time of presentation.

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On examination, the patient was found to be normotensive but obese. He had mild prognathism, and his hands appeared enlarged. Otherwise, the physical examination was normal.

Subsequent laboratory studies revealed a growth hormone (GH) level of 12 ng per mL (12 [micro]g per L) and an insulin-like growth factor I (IGF-I) of 992 U per mL; testosterone and prolactin levels were normal. An oral glucose tolerance test with GH determinations demonstrated a lack of GH suppression consistent with acromegaly (Figure 2). Magnetic resonance imaging (MRI) revealed a 1.1-cm pituitary adenoma (Figure 3).

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The patient underwent transsphenoidal resection of the pituitary tumor. By six months after surgery, the patient had experienced slight regression of soft tissue enlargement. Repeat assays revealed an undetectable GH level and a normal IGF-I level. An oral glucose tolerance test with GH determinations showed suppression of GH. MRI revealed no evidence of residual tumor (Figure 3).

Clinical Characteristics

As evidenced by the illustrative case, acromegaly is largely diagnosed on the basis of careful clinical observation and questioning of the patient.(1) No data are available on the prevalence of acromegaly in the United States, and the exact incidence has been difficult to ascertain, because the disorder often is not diagnosed until five to 15 years after onset.(2) The average family physician is unlikely to encounter more than one case of acromegaly in a career.

Acromegaly has no sexual predilection, and most cases are diagnosed in the third through fifth decades.(3) Characteristic signs and symptoms result from four common but slowly evolving problems: excessive secretion of GH, mass effect of an enlarging pituitary adenoma, destruction of other pituitary tissue and cosecretion of other pituitary hormones.

Common clinical features of acromegaly are listed in Table 1.(3)(4) Notably absent is the increased linear growth of long bones that is the manifestation of giantism when it begins in childhood, before closure of the metaphyseal growth plates.

TABLE 1 Clinical Manifestations of Acromegaly

Derived from references 3 and 4.

Somatomedins are responsible for the expansion of soft tissue structures in patients with acromegaly. These insulin-like anabolic polypeptides are produced by the liver and target tissues and are controlled by GH production in the anterior pituitary (adenohypophysis). Although excessive GH production from adenomatous hyperplasia of the pituitary accounts for 99 percent of all cases of acromegaly,(5) additional etiologic factors include ectopic production of growth hormone-releasing factor (GHRF) by other tumors (breast, stomach, lung),(6) ectopic pharyngeal pituitary tissue(7) and increased or ectopic production of growth hormone-releasing hormone (GHRH).(8)(9)

Somatomedins act to increase the mitogenic activity of growing tissues. Tissues and organs that contain a large amount of cartilage proteoglycans are most prominently affected, but cortical bone can also enlarge. GH works indirectly to produce an anti-insulin effect and to alter lipid metabolism, which explains why 29 to 45 percent of patients with acromegaly also have glucose intolerance, frank diabetes mellitus and/or hypercholesterolemia.(10)

Much less well understood is the pathogenesis of hypertension,(11) cardiomyopathy and arrhythmias(12) in patients with acromegaly. These cardiovascular complications correlate with the duration of acromegaly but not with GH levels. Cardiovascular complications can be refractory to standard management and are the leading cause of death in patients with acromegaly.(13)(14)

Cholelithiasis occurs in 70 percent of patients with acromegaly.(15) Careful surveillance is required, because patients with acromegaly also are at increased risk of colonic polyposis and colon cancer.(16)

Destruction of normal pituitary tissue by macroadenomas (tumors greater than 1 cm in diameter) can result in hormone deficiencies. Oligomenorrhea or amenorrhea secondary to low gonadotropin levels(15) or the lactogenic effect of GH(17) occurs in 40 percent of women with acromegaly. Conversely, mixed pituitary adenomas occur in 15 percent of patients with acromegaly. If these tumors also secrete prolactin, they can cause such problems as menstrual disorders and erectile dysfunction.(18)

Expansion of growing pituitary tissue can cause many problems with local structures. Perhaps the best recognized of these problems is bitemporal loss of vision, which can occur when the pituitary tissue encroaches on the medial crossing nerve fibers at the optic chiasm. Other visual field deficits can also occur.

Invasion of the neighboring cavernous sinus may produce palsies of the extraocular muscles if the nerves are compressed. Being the most medial, the sixth cranial nerve (abducent nerve) is especially vulnerable, and impingement on this nerve can produce an inability to abduct the ipsilateral eye. Overall, headache is the most common complaint. Although posterior pituitary involvement from impingement or invasion is rare, diabetes insipidus can occur and must be differentiated from the diabetes mellitus that may be associated with acromegaly.

Confirming the Diagnosis

A thorough and systematic neuroendocrine evaluation is necessary to confirm the diagnosis of acromegaly. The results of this investigation may directly influence the prognosis and treatment of this disease. A suggested approach to the diagnosis and management of acromegaly is given in Figure 4.

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ENDOCRINOLOGIC STUDIES

While it is important to assess GH levels, potential pitfalls must be recognized. Random blood samples are notoriously unreliable because of the pulsatile secretion of GH in both normal and pathologic conditions, including stress, diabetes mellitus, renal failure and malnutrition.

A more reliable hormonal measure is the serum level of IGF-I (formerly called somatomedin C), since IGF-I is secreted in a nonpulsatile fashion on stimulation by GH. Except in pregnant or pubertal patients, a single elevated IGF-I measurement is virtually diagnostic for acromegaly.(19) Furthermore, serial measurements of IGF-I can be used to monitor disease activity and response to therapy.

If both IGF-I and GH levels are normal but acromegaly is suspected clinically, a provocation test should be performed. The most reliable test is glucose suppression of GH through inhibition of its insulin counterregulatory function. This test is performed by administering 100 g of glucose to a patient who has fasted overnight. Serum glucose and GH levels are measured before the glucose is administered and then remeasured every 30 minutes for a total of two hours. The GH level normally is suppressed to less than 2 ng per mL (2 [micro]g per L). Failure of glucose to suppress GH to less than 2 ng per mL two hours after the administration of a 100-g glucose load in the fasting state is detected in nearly all patients with acromegaly.(15)

Less well-studied tests include GH augmentation by thyrotropin-releasing hormone and GH suppression by levodopa or dopamine administration.(20) A GHRF assay is also available, but this test appears to be useful only in patients with acromegaly caused by ectopic hormone production, hypothalamic dysfunction or tumors. Finally, since plurihormonal pituitary tumors may exist, assessment of other hormone levels, such as serum prolactin, luteinizing hormone, follicle-stimulating hormone and thyroxine levels, may be indicated.(15)

RADIOLOGIC STUDIES

Radiologic studies are essential for determining the site of pathology in the patient with acromegaly. If a large tumor is present, skull and sinus radiographs may demonstrate enlargement of the sella turcica or erosion of the sphenoid bone. If metastatic bronchial carcinoid or small cell carcinoma of the lung is suspected, high-resolution computed tomographic (CT) scanning or MRI is indicated.

At present, enhanced CT scanning or MRI should be used to evaluate all patients suspected of having a pituitary tumor. MRI is especially sensitive in detecting microadenomas, and it can reveal information that is important in planning treatment.(20)

Treatment of Acromegaly

Acromegaly remains a therapeutic challenge. The three primary modes of treatment are surgery, radiotherapy and medical treatment.

SURGERY

Surgical intervention is the most common approach when a pituitary tumor is demonstrated. The best results are achieved when the neurosurgeon has extensive experience in transsphenoidal microsurgery.

Microsurgical techniques have produced acceptable results in patients with noninvasive microadenomas. With microsurgery, "cure" rates--defined by clinical improvement and GH levels below 5 ng per mL (5 [micro]g per L)--have been achieved in 56 to 60 percent of patients. Iatrogenic hypopituitarism develops in 5 to 17 percent of patients, and the surgery has an overall correctable complication rate of 7 to 20 percent.(21)

Patients with larger tumors, very high preoperative GH levels and high-grade tumors have poorer outcomes. In these patients, cure rates range from 22 to 41 percent.(22)(23)

RADIOTHERAPY

Radiotherapy has been used as a primary treatment and as an adjunctive treatment following incomplete surgical removal of pituitary adenomas. As a primary treatment, radiotherapy is effective in reducing GH levels; however, the results are usually appreciated over the course of several years.

Standard external-beam supervoltage irradiation with delivery of 4,500 to 5,000 rad over a five- to six-week period can be expected to produce a 50 percent reduction in GH levels at two years and a 15 percent reduction every year thereafter.(24) For a large tumor that may be impinging on an important structure, this rate of improvement is unacceptable. Furthermore, unusual but serious complications of radiotherapy include panhypopituitarism with destruction of normal glandular tissue and cerebral or optic nerve radionecrosis.

Interstitial,(25) alpha particle(26) and proton beam irradiation(27) may prove to be more effective primary treatment than standard external-beam irradiation. Since these forms of radiotherapy are not yet widely available, they have not been fully evaluated.

Perhaps conventional radiotherapy may be best used as an adjunct to surgery. It may be used as the primary treatment when the patient's age or medical condition precludes safe surgical removal of the adenoma.

DRUG TREATMENT

Based on observations that dopamine suppresses GH in patients with acromegaly, a great deal of attention has been focused on the use of various chemical agents to control the release of hormones and the growth of tumors. Treatment with high-dose estrogens, progestins, chlorpromazine (Thorazine) and other drugs has been explored, but the most extensively used agent has been the dopamine agonist bromocriptine (Parlodel).

In a summary(15) of clinical trials using bromocriptine in dosages ranging from 2.5 to 80 mg per day, approximately 70 percent of patients reported subjective improvement in symptoms, although only 21 percent demonstrated GH reductions to below 5 ng per mL (5 [micro]g per L).(12) To date, however, objective trials of bromocriptine therapy in patients with acromegaly have not been performed, and tumor shrinkage has not been radiographically confirmed.

Bromocriptine can be initiated in a dosage of 1.25 mg per day, taken at bedtime. The dosage is increased in increments every three or four days until a dosage of 20 to 60 mg per day is achieved. Side effects may include nausea, constipation and emotional lability. If more serious problems, such as hypotension and cold-induced vasospasm, occur, the dosage should be reduced. While an acute decline in GH levels after a 5-mg dose of bromocriptine may predict satisfactory results, there are actually no reliable pretreatment predictors of a favorable outcome for bromocriptine therapy alone. Consequently, therapy must be approached on a trial basis for each patient.

More promising are the long-acting somatostatin analogs. Studies(15) have found that GH levels declined significantly in 80 percent of patients with acromegaly who were treated with synthetic octopeptides such as octreotide (Sandostatin). Improvement of symptoms has been reported in 60 to 70 percent of patients. Common side effects of somatostatin analogs include steatorrhea and cholelithiasis (generally asymptomatic).(28)

The U.S. Food and Drug Administration has not yet approved the use of long-acting somatostatin analogs for the treatment of acromegaly. In Europe, however, these agents have been shown to be extremely effective as adjunctive therapy both before and after surgery.(15)

Treatment of Associated Problems

Hypertension in a patient with acromegaly is best treated with the usual measures, including weight reduction, dietary measures and oral antihypertensive medications. Diabetes mellitus is generally controlled with the reduction of GH levels; indeed, improvement in glucose tolerance has been reported in 75 to 82 percent of patients treated with bromocriptine.(29) Arrhythmias may be secondary to associated ischemic or hypertensive cardiomyopathies, or they may be a direct effect of GH. Rhythm disturbances can be managed with standard antiarrhthymic agents, although it is also essential to correct acromegaly and associated diabetes and hypertension.

REFERENCES

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(2.)Nabarro JD. Acromegaly. Clin Endocrinol 1987; 26:481-512.

(3.)Wilson JD, et al., eds. Harrison's Principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991:1660-4.

(4.)Rubenstein E, Federman DD, eds. Scientific American medicine. Vol. 3. New York: Scientific American, 1993:7-9.

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(6.)Asa SL, Scheithauer BW, Bilbao JM, Horvath E, Ryan N, Kovacs K, et al. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor. J Clin Endocrinol Metab 1984; 58:796-803.

(7.)Corenblum B, LeBlanc FE, Watanabe M. Acromegaly with an adenomatous pharyngeal pituitary. JAMA 1980; 243:1456-7.

(8.)Sano T, Asa SL, Kovacs K. Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations. Endocr Rev 1988; 9:357-73.

(9.)Frohman LA, Downs TR. Ectopic GRF syndromes. In: Robbins RJ, Melmed S, eds. Acromegaly: a century of scientific and clinical progress. New York: Plenum, 1987:115-25.

(10.)Jadresic A, Banks LM, Child DF, Diamant L, Doyle FH, Fraser TR, et al. The acromegaly syndrome. Relation between clinical features, growth hormone values and radiological characteristics of the pituitary tumours. QJ Med 1982; 51:189-204.

(11.)Ritchie CM, Sheridan B, Fraser R, Hadden DR, Kennedy AL, Riddell J, et al. Studies on the pathogenesis of hypertension in Cushing's disease and acromegaly. QJ Med 1990; 76:855-67.

(12.)Kahaly G, Stover C, Beyer J, Mohr-Kahaly S. Relation of endocrine and cardiac findings in acromegalics. J Endocrinol Invest 1992; 15:13-8.

(13.)Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 1988; 223:327-35.

(14.)Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. QJ Med 1970; 39:1-16.

(15.)Barkan AL. Acromegaly. Diagnosis and therapy. Endocrinol Metab Clin North Am 1989; 18:277-310.

(16.)Brunner JE, Johnson CC, Zafar S, Peterson EL, Brunner JF, Mellinger RC. Colon cancer and polyps in acromegaly: increased risk associated with family history of colon cancer. Clin Endocrinol 1990; 32:65-71.

(17.)Fradkin JE, Eastman RC, Lesniak MA, Roth J. Specificity spillover at the hormone receptor--exploring its role in human disease. N Engl J Med 1989; 320:640-5.

(18.)Scheithauer BW, Kovacs K, Randall RV, Horvath E, Laws ER Jr. Pathology of excessive production of growth hormone. Clin Endocrinol Metab 1986; 15:655-81.

(19.)Clemmons DR, Van Wyk JJ, Ridgway EC, Kliman B, Kjellberg RN, Underwood LE. Evaluation of acromegaly by radioimmunoassay of somatomedin-C. N Engl J Med 1979; 301:1138-42.

(20.)Wilson JD, Foster DW, eds. Williams' Textbook of endocrinology. 8th ed. Philadelphia: Saunders, 1992:273-4.

(21.)Ross DA, Wilson CB. Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenoma in a series of 214 patients. J Neurosurg 1988; 68:854-67.

(22.)Arafah BM, Brodkey JS, Pearson H. Acromegaly. In: Santen RJ, Manni A, eds. Diagnosis and management of endocrine-related tumors. Boston: Nijhoff, 1984:45-61.

(23.)Grisoli F, Leclercq T, Jaquet P, Guibout M, Winteler JP, Hassoun J, et al. Transsphenoidal surgery for acromegaly--long-term results in 100 patients. Surg Neurol 1985; 23:513-9.

(24.)Eastman RC, Gordon P, Roth J. Radiation therapy of acromegaly. Endocrinal Metab Clin North Am 1992; 21:693-712.

(25.)Cassar J, Doyle FH, Banks LM, Jadresic A, Mashiter K, Joplin GF. Interstitial pituitary irradiation with 90Y for the treatment of acromegaly. A reappraisal. Acta Endocrinol 1981; 96:295-300.

(26.)Linfoot JA. Alpha particle pituitary irradiation in the primary and post-surgical management of pituitary microadenomas. In: Faglia G, Giovanelli MA, McLeod RM, eds. Pituitary microadenomas. New York: Academic, 1980:515-29.

(27.)Kilman B, Kjellberg RN, Swisher B. Proton beam therapy of acromegaly: a 20-year experience. In: Black PM, Zervas NT, Ridgeway EC, eds. Secretory tumors of the pituitary gland. New York: Raven, 1984:191-211.

(28.)Sassolas G. The role of Sandostatin in acromegaly. Metabolism 1992; 41(9 Suppl 2):39-43.

(29.)Clayton RN, Vrionides Y, Lynch SS, Butt WR, London DR. Response of acromegaly to long term bromocriptine therapy: a biochemical and clinical assessment. Acta Endocrinol 1978; 89:469-82.

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