Introduction

Acromegaly is a medical condition defined by elevated serum growth hormone (GH) levels almost always secondary to hypersecretion by cells of the anterior pituitary. Descriptions of individuals consistent with the clinical picture of acromegaly have been recorded throughout history. Modern scientists are retrospectively considering familiar cases of either known or suspected acromegaly dating back to biblical times. The first clinical description of acromegaly was published by Johannes Wierus in 1567, but the establishment of the diagnosis and coining of the name “acromegaly” by Pierre Marie would not occur until more than 300 years later. The idea that specific hyperfunctioning pituitary endocrine cells were responsible and the subsequent emergence of effective treatments for the condition through pituitary surgery (and radiotherapy) would follow soon thereafter in the early twentieth century.

Though the mechanism of acromegaly had been theorized previously, the molecular structure of growth hormone had not been known nor was the hormone isolated until 1945. Since then, it has become clear that 98% of cases of acromegaly are caused by pituitary hypersecretion of growth hormone and more than 90% of acromegalics harbor a benign GH-secreting pituitary adenoma. The remaining 2% are due to elevated GH levels from GH-secreting extrapituitary tumors or secondary to elevated GH-releasing hormone.

The annual incidence of acromegaly is 3 to 4 cases per million and the overall prevalence is approximately 60 per million. In the United States, between 700 and 900 cases are diagnosed every year. Due to the insidious onset and relative rarity of the disease, early diagnosis of acromegaly can be difficult. Mean delay in diagnosis is between 7 to 10 years from first symptoms of onset. Thus, more than 75% of GH-secreting pituitary tumors are macroadenomas (>10 mm) at presentation. Common systemic signs and symptoms associated with the condition are summarized in Table 20-1 . Along with the specific clinical sequelae of the disease, acromegaly is associated with many coexisting morbidities, including diabetes mellitus, hypertension, cardiomyopathy, sleep apnea, and colon cancer. Although the vast majority of pituitary tumors including those causing acromegaly are benign, the systemic effects of chronically elevated GH and IGF-1 cause significant morbidity ( Table 20-2 ). Diagnosis of acromegaly carries a twofold to fourfold increase in mortality. In untreated acromegaly, cardiovascular complications are responsible for 60% of the mortality followed in frequency by respiratory disease (25%) and cancer (15%). Mortality risk decreases if insulin-growth factor 1 (IGF-1) and GH levels are effectively normalized, highlighting the importance for prompt and effective treatment strategies. Prevention of the systemic morbidity and mortality associated with elevated GH and IGF-1 levels is the main indication for aggressive treatment of the disease.

Ideal treatment for this disabling condition involves reduction of tumor size, suppression of hormone hypersecretion, low recurrence rate, and preservation of normal pituitary function. At present, the therapeutic modality that most effectively satisfies these treatment goals is surgical. In this chapter, we review the role of pituitary surgery in the management of acromegaly.

Clinical Evaluation

The first indication to begin diagnostic testing is based on clinical suspicion of the disease. A few general sets of guidelines with indications for heightened clinical suspicion have been published in recent years, outlined in Table 20-1 . Approximately 40% of patients are first diagnosed by an internist or family physician and 20% are diagnosed by an endocrinologist. Once clinical suspicion is kindled, patients must undergo laboratory testing to establish biochemical evidence of disease. Though elevated serum GH levels due to hypersecreting pituitary-somatotrope adenoma cells are usually thought of as the primary cause of acromegaly and are uniformly elevated in the disease, GH levels alone are misleading owing to the variable pulsatile GH secretion pattern in normal subjects and sensitivity to variables such as sleep, stress, and nutritional status. It is necessary to measure both GH and IGF-1 levels when acromegaly is suspected clinically. IGF-1 levels are generally measured first and compared with established age and gender-matched norms because their elevation almost always accompanies GH hypersecretion and is a sensitive and specific marker for GH hypersecretion. Serum IGF-1 has a longer half-life than GH and since the GH-IGF-1 correlation is log-linear, IGF-1 levels do not fluctuate as much as GH, which makes it a good marker to approximate overall GH elevation. Thus a normal IGF-1 essentially rules out acromegaly. In doubtful cases, administration of a 75 g oral glucose load to test GH suppression can be performed (oral glucose tolerance test [OGTT]). Acromegalics show failure to suppress GH secretion to an appropriately low nadir at 0, 30, 60, 90, and 120 minutes following an oral glucose load. Adequate GH suppression, even in the presence of an elevated IGF-1, essentially rules out acromegaly. Inadequate GH suppression confirms the diagnosis.

Some degree of controversy has existed over the biochemical threshold for diagnosis for basal GH, OGTT GH, and IGF-1 levels. For example, laboratory measurement of growth hormone is continually evolving such that more sensitive GH measurement is possible, potentially allowing lower thresholds for diagnosis. Still, the diagnostic OGTT GH nadir using standard commercial assays remains for now at <1 µg/L. Rare instances of acromegaly exist that are not caught by generally accepted diagnostic testing and criteria, and in these cases diagnosis is a challenge.

A subsequent pituitary MRI will aid the management decision. Pituitary microadenomas (<10 mm in diameter) classically appear hypointense on T1-weighted imaging, may have variable appearance on T2-weighted MRI, and are hypointense after gadolinium contrast. Macroadenomas (>10 mm in diameter), however, are relatively isointense on T1 ( Figure 20-1, A ) and T2-weighted MRI and can be hypointense ( Figure 20-1, B ) or hyperintense after gadolinium administration.

A 54-year-old female was evaluated for acromegalic features. Serum IGF-1 and GH levels confirmed the diagnosis of acromegaly . A, Coronal T1-weighted MRI shows an isointense macroadenoma measuring 14 × 18 mm. B, After gadolinium administration . C, Postoperative T1-weighted MRI with contrast, coronal section, does not show gross evidence of residual tumor. However, the patient’s serum GH and IGF-1 levels remained slightly elevated. Supplemental medical therapy was administered with normalization of the laboratory data.

Indications for Surgery

Surgical resection of a pituitary tumor was chronologically the first treatment attempted by early physicians for acromegaly and for most patients remains the first line of therapy. Surgical resection offers several advantages over pharmacological or radiotherapy. First, physical removal of hypersecreting tissue offers the best chance for cure. Second, both medical and radiation therapy often require a long time to effectively suppress GH and IGF-1 levels to normal, by which point the mortality benefit of treatment may be partially or wholly obviated since disease duration and age predict higher mortality, whereas GH levels can drop almost immediately following surgery. The issue of patient selection for surgery has been revisited frequently and remains a topic of ongoing debate. Transsphenoidal resection appears to be first-line treatment for intrasellar microadenomas, noninvasive macroadenomas, and in the context of compression on neighboring structures. Surgery is not recommended if the lesion cannot be definitively identified or if the patient’s general medical condition is such that the risk of surgery may obviate the potential benefits.