The views expressed in the article are those of the authors and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US Government.

Acromegaly results from hypersecretion of growth hormone or growth hormone–releasing hormone. In the majority of patients, the underlying cause is a pituitary somatotroph adenoma. Characteristic features include frontal bossing, protruding jaw, coarse facial features, a wide nasal bridge, and thick lips. Despite such obvious manifestations, the variety of presentations and the insidious course of the disease can delay the diagnosis for years. The longer the disease progresses, the greater the risk of complications that will affect the cardiovascular, musculoskeletal, respiratory, neurologic, and endocrine systems. Effective treatments are available.

Acromegaly is a clinical syndrome that results from the excessive secretion of growth hormone (GH) or GH-releasing hormone.¹ The GH hypersecretion, in turn, stimulates the production of insulinlike growth factor-I (IGF-I). Increased levels of both GH and IGF-I are responsible for the physical signs and symptoms of the disorder.² Acromegaly is a rare condition, with an annual incidence of 3 to 4 cases per million population,³ and a prevalence that varies from 46 to 75 cases per 1 million.⁴

Acromegaly often presents with acral and facial changes, endocrine abnormalities, headaches, visual changes, hypertension, sleep apnea, and carpal tunnel syndrome.⁴ The variety of presentations of acromegaly often can delay diagnosis and result in excess morbidity and mortality.

Illustrative Case

A 28-year-old Hispanic man with newly diagnosed hypertension presented to the internal medicine clinic for routine follow-up. He was generally without complaints, except for a long-standing history of snoring and some recent apneic events noted by his wife. The patient denied any changes in his appearance or in his ring or hat size.

However, when comparing his driver's license photo taken 4 years earlier, the man's current facial features were more prominent than then. He had no visual disturbances or diplopia. His current medications included lisinopril (Prinivil, Zestril) 10 mg/day for hypertension and rabeprazole sodium (Aciphex) 20 mg/day for gastroesophageal reflux disease.

Physical examination showed a well-built, 5'9" man weighing 220 lb; blood pressure, 122/64 mm Hg; pulse, 75 beats/min. He had large facial features, with frontal bossing and a prominent jaw (Figure 1). His hands were large, with sausagelike digits (Figures 2, 3). He had a Mallampati class IV airway with macroglossia, and his neck size was 17 inches. No other abnormalities were noted.

Figure 1—The large facial features, with frontal bossing and a prominent jaw, in this man aroused suspicion for acromegaly.

Figure 2—Large hands, with sausagelike digits, are classic features of acromegaly.

Figure 3—Plain-film radiograph showing slight joint space widening and distal tufting of the phalanges in a patient with acromegaly.

Laboratory test results showed elevated levels of IGF-I (1310 ng/mL; normal, 100-402 ng/mL) and of plasma GH (12.6 ng/mL; normal, 0.7-6.0 ng/mL) that did not suppress with an oral glucose tolerance test. His postglucose challenge GH levels were 17.8 ng/mL and 13.5 ng/mL (normal, < 1 ng/mL). Laboratory values were also notable for a mildly elevated fasting glucose level (104 mg/dL), bicarbonate (32 mEq/L), and phosphate (4.7 mg/dL). The patient was diagnosed with acromegaly based on these results.

Polysomnography also revealed he had obstructive sleep apnea. Magnetic resonance imaging studies revealed an enlarged sella, with an enlarged pituitary gland and concomitant enlargement of the suprasellar cistern consistent with acromegaly. The patient was referred to the endocrinology department and was started on therapy with octreotide LAR (Sandostatin), titrated up to 40 mg monthly, in the attempt to suppress the IGF-I, which did not occur. His last IGF-I level was 912 ng/mL before he moved out of the area.

Etiology

More than 99% of cases of acromegaly are caused by hyperplasia of GH-secreting cells in the pituitary associated with a pituitary somatotroph adenoma.^2,5 The remainder of cases has an ectopic etiology. Despite originating in the anterior pituitary, many of these benign tumors present with parasellar or suprasellar invasion.⁶

The hormonal effects of acromegaly can have many disfiguring and serious complications that develop over time. Signs and symptoms typically progress slowly, thereby often delaying the diagnosis for up to 10 years.⁶ Because of the excessive GH secretion, patients undergo soft-tissue and bony changes of the facial and acral areas. Expansion of all dimensions of the neurocranium and orofacial skeleton, except for the maxilla, results in cranial enlargement, with protrusion of the supraorbital ridges, mandibular prognathism, and a deep bite.⁷ Patients also exhibit uvula and pharyngeal enlargement, the latter often leading to gradual voice changes. Oversized hands and feet are typical,² as was seen in our patient.

Associated Complications

The list of conditions associated with acromegaly is long. Relative frequencies of these conditions in patients with acromegaly are listed in the Table.^3,4,8-17 The increased frequency of cardiovascular disease, hypertension, diabetes, sleep apnea, and gastrointestinal cancer in patients with acromegaly shortens life expectancy; overall mortality rates are twice as high as those in age-matched controls.¹⁸

Hypertension is present in approximately 46% of patients with acromegaly compared with 25% of the general population, presumably secondary to volume overload induced by the increased GH and IGF-I levels.¹⁵ The exact pathogenesis of hypertension in acromegaly, however, is yet to be elucidated. Hypertension often persists after patients have been successfully treated, suggesting that other underlying mechanisms, such as essential hypertension, may be at work.²

Cardiovascular disease is most often manifested in this patient population as biventricular hypertrophy, which in long-standing disease can lead to diastolic dysfunction and eventually to systolic dysfunction. Ectopic ventricular beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia, and bundle-branch blocks are seen in up to 40% of patients at the time of diagnosis.⁸ Mitral and aortic valve abnormalities affect up to 86% of patients with active acromegaly.¹¹ It is the increased incidence of hyperlipidemia, hypertension, and insulin resistance that puts these patients at increased risk for heart disease.

As many as 75% of patients also have sleep apnea.¹² Two thirds of patients have an obstructive etiology, while one third have a central nervous system origin (ie, cessation of respiratory movements).¹³ Obstruction may be due to tissue hypertrophy, macroglossia, and/or jaw deformity, all of which can contribute to an anatomic narrowing of the upper airway. Central sleep apnea is thought to be due to direct effects of GH on the brain's breathing center. Treatment of acromegaly often decreases the severity of sleep apnea.⁸

The other respiratory complications of acromegaly are less understood. Emphysema has been described and is thought to be due to increased lung volume and compliance, and elongation and divergence of the rib cage, which lead to a barrel chest. Vertebral bodies enlarge and elongate, stiffening the rib cage, while thoracic spine kyphoscoliosis can shorten inspiratory time.⁸ For these reasons, patients with acromegaly often have difficulty meeting the aerobic demands of exercise.

Insulin resistance is seen in up to 54% of patients; impaired fasting glycemia accounts for 15%, impaired glucose tolerance for 25%, and overt diabetes mellitus for 15% of cases.⁸ GH excess has been shown to induce insulin resistance by impairing the ability of insulin to suppress glucose production and stimulate glucose utilization.⁸ Reduced sensitivity to insulin is thought to be an important physiologic feature of most patients with acromegaly.¹⁹ Although the extent of reduction in insulin sensitivity is similar in both normal glucose tolerant and impaired glucose tolerant or diabetic patients with acromegaly, the normal glucose tolerant acromegalic patients appear to be able to compensate with a hypersecretion of insulin. This suggests that beta-cell function in response to a reduction in insulin sensitivity may determine the status of glucose tolerance in acromegaly.¹⁹

Common Manifestations

Arthropathy is the most frequent complaint at the time of diagnosis.⁸ Pain is the most common symptom of arthropathy, and crepitus is the most common sign.⁸ Although our patient initially denied joint problems, in retrospect he recalled having increasing pain in his hands, feet, knees, and hips.

In 50% of patients, plain film radiographs will demonstrate changes in the hands. Joint-space widening is the earliest finding, followed by distal tufting of the phalanges, osteophyte formation, enthesopathy, and calcification of the joint capsule.⁸

Figure 3 demonstrates the slight widening of the joint space and the distal tufting of the phalanges in our patient. Although acromegalic arthropathy is generally noninflammatory, features of osteoarthritis frequently develop in later stages of the disease. At this late stage, acromegalic arthropathy cannot be further improved with GH and IGF-I suppression.⁸

Hypertrophy of the jaw, or prognathism, which often leads to an increase in the interdental spaces, can produce temporomandibular joint pain. This is why oral surgeons and dentists are often the sources of referral for evaluation. Additional rheumatologic manifestations include carpal tunnel syndrome.⁸

Treatment

As always, early diagnosis and effective treatment can reduce morbidity and mortality. The goal of therapy is to reverse the effects of GH hypersecretion and to normalize IGF-I levels. Surgical resection of the pituitary adenoma is the treatment of choice for most patients with acromegaly. Transsphenoidal surgery is the preferred method for microadenomas (≤10 mm in diameter) and for macroadenomas (>10 mm).²

Somatostatin analogs, such as octreotide acetate, may be used as adjuvant therapy or as primary treatment in certain patients, including those who refuse surgery or who have medical contraindications to surgery, and those who prefer pharmacotherapy.²

Dopamine agonists, such as bromocriptine mesylate (Parlodel) and cabergoline (Dostinex), can also lower GH levels but are not well tolerated; these agents are generally reserved for patients who have associated hyperprolactinemia.²

Radiotherapy can also be used as adjuvant therapy for residual disease after surgery and/or for treatment of disease that is poorly responsive to medical therapy. Patients may benefit from medical therapy while awaiting the effects of irradiation.² Pegvisomant (Somavert), a GH-receptor antagonist, is approved by the Food and Drug Administration for the treatment of acromegaly that is not responsive to other treatment. The 20-mg dose has been shown to return IGF-I levels to normal in 89% of patients at the end of 12 weeks of therapy, as well as to improve the signs and symptoms of acromegaly compared with placebo.²⁰

Conclusion

Acromegaly presents with a wide variety of symptoms, often resulting in missed or delayed diagnosis. The 28-year-old patient we describe was brought to medical attention because of his hypertension. Only after several evaluations for hypertension (with different physicians), was the patient successfully diagnosed with acromegaly, along with some of the known associated comorbidities—obstructive sleep apnea, glucose intolerance, and hyperphosphatemia. Awareness of the characteristic facial features and comorbidities associated with acromegaly can help increase the recognition of this condition.

The diagnosis is best made by looking at and listening to the patient, while also comparing current features with old photographs. Clinical suspicion may be confirmed by evaluating for elevated serum IGF-I levels and by measuring GH levels after an oral glucose load.

SELF-ASSESSMENT TEST

1. Which of the following statements about acromegaly is not true?

1. Most cases are due to GH hypersecretion
2. The diagnosis is usually obvious
3. Patients may experience a gradual change in their voice
4. Enlarged hands and feet are typical

2. All these comorbidities are common with acromegaly, except:

1. Sleep apnea
2. Insulin resistance
3. Obesity
4. Biventricular hypertrophy

3. What is the most common complaint at the time of diagnosis?

1. Hypertension
2. Swallowing difficulties
3. Daytime drowsiness
4. Arthropathy

4. All these diagnostic measures are indicators of acromegaly, except:

1. Increased IGF-I level
2. Increased plasma GH level
3. GH level does not suppress postglucose load
4. Joint space narrowing on x-rays of the hands

5. Which of these treatments is best for a 35-year-old patient with a small pituitary adenoma?

1. Octreotide
2. Radiation
3. Surgery
4. Bromocriptine

(Answers at end of references list)

References

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2. AACE Acromegaly Guidelines Task Force. AACE Medical Guidelines for Clinical Practice for the diagnosis and treatment of acromegaly. Endocr Pract. 2004;10:213-225.
3. Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary. 1999;2:29-41.
4. Mestrón A, Webb SM, Astorga R, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia, REA). Eur J Endocrinol. 2004;151:439-446.
5. Morel O, Giraud P, Bernier MO, et al. Ectopic acromegaly: localization of the pituitary growth hormone-releasing hormone producing tumor by In-111 pentetreotide scintigraphy and report of two cases. Clin Nucl Med. 2004;29:841-843.
6. Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med. 1998;129:472-483.
7. Dostálová S, Sonka K, Smahel Z, et al. Cephalometric assessment of cranial abnormalities in patients with acromegaly. J Craniomaxillofac Surg. 2003;31:80-87.
8. Colao A, Ferone D, Marzullo P, et al. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25:102-152.
9. Giusti M, Gussoni G, Cuttica CM, et al. Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly: six-month report on an Italian multicenter study. J Clin Endocrinol Metab. 1996;81:2089-2097.
10. Cheung NW, Boyages SC. The thyroid gland in acromegaly: an ultrasonographic study. Clin Endocrinol (Oxf). 1997;46:545-549.
11. Colao A, Spinelli L, Marzullo P, et al. High prevalence of cardiac valve disease in acromegaly: an observational, analytical, case-control study. J Clin Endocrinol Metab. 2003;88:3196-3201.
12. Weiss V, Sonka K, Pretl M, et al. Prevalence of the sleep apnea syndrome in acromegaly population. J Endocrinol Invest. 2000;23:515-519.
13. Grunstein RR, Ho KY, Sullivan CE. Sleep apnea in acromegaly. Ann Intern Med. 1991;115:527-532.
14. Colao A, Marzullo P, Spiezia S, et al. Effect of growth hormone (GH) and insulin-like growth factor I on prostate diseases: an ultrasonographic and endocrine study in acromegaly, GH deficiency, and healthy subjects. J Clin Endocrinol Metab. 1999; 84:1986-1991.
15. Vitale G, Pivonello R, Auriemma RS, et al. Hypertension in acromegaly and in the normal population: prevalence and determinants. Clin Endocrinol (Oxf). 2005;63:470-476.
16. Fukuda I, Hizuka N, Murakami Y, et al. Clinical features and therapeutic outcomes of 65 patients with acromegaly at Tokyo Women's Medical University. Intern Med. 2001;40:987-992.
17. Bihan H, Espinosa C, Valdes-Socin H, et al. Long-term outcome of patients with acromegaly and congestive heart failure. J Clin Endocrinol Metab. 2004;89:5308-5313.
18. Holdaway IM, Rajasoorya CR, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004; 89:667-674.
19. Kasayama S, Otsuki M, Takagi M, et al. Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients. Clin Endocrinol (Oxf). 2000; 52:549-555.
20. Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000;342:1171-1177.

Answers: 1. B; 2. C; 3. D; 4. D; 5. C.