Approach Considerations
Patients with active acromegaly have abnormal dynamics of GH secretion. Before immunoassays for insulinlike growth factor I (IGF-I) were developed, growth hormone (GH) measurement was the only method used in the biochemical assessment of the disease. [27] (A simple diagnostic approach is to measure serum GH 1 hour after oral administration of 100 g of glucose.) [28]
IGF-I, however, has been the most reliable biochemical indicator of acromegaly, because of an excellent linear dose-response correlation between serum IGF-I levels and 24-hour integrated GH secretion.
Laboratory Studies
Oral glucose
Because GH secretion is inhibited by glucose, measurement of glucose nonsuppressibility may be useful, although there is debate as to what value of GH is considered “normal” after a 1.75g/kg oral glucose challenge (not to exceed 75 g oral glucose load). A paradoxic rise in GH concentration is seen in 15-20% of patients with acromegaly following oral glucose administration.
Two baseline GH levels are obtained prior to ingestion of 75 or 100 g of oral glucose, and additional GH measurements are made at 30, 60, 90, and 120 minutes following the oral glucose load.
With newer assays for GH using the immunoradiometric assay (IRMA), acromegaly is thought to be present when a criterion of less than 1 mcg/L is used following oral glucose ingestion.
Growth hormone
Patients with active acromegaly have abnormal dynamics of GH secretion. A simple diagnostic approach is to measure serum GH 1 hour after oral administration of 100 g of glucose. Clearly elevated GH levels (>10 ng/mL) after oral glucose, combined with the clinical picture, secure the diagnosis of acromegaly, while a normal GH level (< 5 ng/mL) after oral glucose essentially excludes the diagnosis.
Only a small percentage of patients investigated for acromegaly have a postglucose GH level that is intermediate (5-10 ng/mL). In these patients, other tests can be used to define their status.
Before immunoassays for IGF-I, GH measurement was the only method used in the biochemical assessment of acromegaly, [27] and the availability of supersensitive GH has changed many aspects of the interpretation of the GH value. Hypersecretion and abnormal neuroregulation characterize acromegaly. GH can be measured in many ways to give useful information on diagnosis, therapy, and prognosis. Measuring GH in the management of acromegaly complements the information IGF-I values provide.
Random GH measurements, however, often are not diagnostic, because of the episodic secretion of GH, its short half-life, and the overlap between GH concentration in individuals with acromegaly and individuals without the condition.
GHRH
GH-releasing hormone (GHRH) concentration may be obtained if clinically indicated. Levels higher than 300 pg/mL usually indicate an ectopic source of GHRH. In pituitary disease (GHRH independent), GHRH concentration is normal or suppressed.
Prolactin
Because as many as 20% of GH-secreting pituitary adenomas co-secrete prolactin, the prolactin level also may be elevated. However, a rise in prolactin may result from stalk compression or from co-secretion from a pituitary adenoma. Pituitary adenomas may be associated with deficiencies of other pituitary hormones. Consider evaluation of the adrenal, thyroid, and gonadal axes.
Insulinlike growth factor I
As previously stated, IGF-I has been the most reliable biochemical indicator of acromegaly. An excellent linear dose-response correlation between serum IGF-I levels and 24-hour integrated GH secretion has been demonstrated. Elevated IGF-I values in a patient whose symptoms prompt appropriate clinical suspicion almost always indicate GH excess. IGF-I is useful not only in diagnosis, but also in monitoring the efficacy of therapy.
Measurement of IGF binding protein 3 (IGFBP-3), the primary binding protein for circulating IGF, is increased in acromegaly and may be useful in its diagnosis. It also may be helpful for monitoring the activity of the disease during treatment.
Factors altering IGF-I levels
Starvation, obesity, and diabetes mellitus decrease IGF-I concentration, while pregnancy increases it. In addition, IGF-I concentrations vary with age, which means an assay is required in which the normal ranges have been stratified to account for this discrepancy.
Potential confusion may arise in the evaluation of healthy adolescents, because IGF-I levels can be substantially higher during puberty than during adulthood. Always compare the patient's measurement with age-matched and sex-matched IGF-I reference ranges published in the literature or established for the specific testing laboratory.
Imaging Studies
MRI
Because of the relatively high incidence of nonfunctioning, incidentally discovered pituitary adenomas, imaging studies should be obtained only after a firm biochemical diagnosis of acromegaly has been made.
The sella turcica should be imaged first, since GH-secreting pituitary adenoma is the most common cause of acromegaly. Magnetic resonance imaging (MRI) is more sensitive than computed tomography (CT) scanning for this purpose and provides detailed information about surrounding structures (eg, optic chiasm, cavernous sinuses).
CT scanning
If MRI findings of the sella are negative, appropriate studies to localize tumors causing ectopic secretion of GH or GHRH may be obtained.
CT scans of the abdomen/pelvis can be used to evaluate for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH. Use chest CT scans to evaluate for bronchogenic carcinoma secreting GH/GHRH.
Radiography
Radiographic studies show the following:
-
Increase in length and thickness of the mandible
-
Underbites resulting from mandible enlargement
-
Thickened calvaria
-
Exaggerated bony ridges and muscle attachments
-
Enlarged frontal, mastoid, and ethmoid sinuses
-
Elongated ribs resulting from proliferation at the cartilage-bone junction
-
Deep barrel chest, which, as a result of continued costal growth, is often pronounced in long-standing acromegaly
-
Periosteal growth of the vertebrae and osteophytic proliferation of the articular margins of joints
-
Cartilage proliferation of the larynx
-
Cortical thickening and distal tufting
-
Deformities of the skull
TRH and GHRH
Although testing with an intravenous administration of thyrotropin-releasing hormone (TRH) is not necessary to make the diagnosis, 50-80% of patients with GH excess have a paradoxic rise in GH levels after the challenge.
Circulating GHRH blood levels may confirm peripheral ectopic GHRH secretion in the presence of an ectopic tumor. However, in the presence of a hypothalamic GHRH-secreting tumor, circulating GHRH levels may be normal.
Histologic Findings
Surgical specimens from pituitary tumors demonstrate a variety of histologic findings, such as the following:
-
Densely granulated somatotrope adenoma
-
Sparsely granulated somatotrope adenoma
-
Mixed somatotrope-lactotrope adenoma
-
Acidophilic stem cell adenoma
-
Mammosomatotroph adenoma
-
Plurihormonal adenoma producing GH and one or more glycoprotein hormones, principally alpha
-
Somatotrope carcinoma
-
Somatotrope hyperplasia
-
No distinct morphologic change
Skin biopsy may demonstrate the following:
-
Slight thinning of the epidermis
-
Papillary and upper reticular dermis (may appear edematous and myxoid)
-
Separation of the collagen fibers
-
Slightly increased number of fibroblasts
-
Fibrous component normal (qualitatively and quantitatively)
-
Dense glycosaminoglycan deposit (most consistent abnormality)
-
Infiltration by glycosaminoglycans (most prominent in the papillary, the upper reticular dermis, and in the vicinity of sweat glands)
Mammosomatotrophs are the most common type of GH-secreting cells involved in childhood gigantism. Coexistence of GH and prolactin in the secretory granules of the tumor cells is clearly demonstrated on immunohistochemical staining.
-
Gigantism and Acromegaly. Image shows a coauthor of this article with a statue of Robert Wadlow, who was called the Alton giant. The tallest person on record, he was 8 feet 11 inches tall at the time of his death.
-
Gigantism and Acromegaly. A 12-year-old boy with McCune-Albright syndrome. His growth-hormone excess manifested as tall stature, coarse facial features, and macrocephaly.
-
Gigantism and Acromegaly. Robert Wadlow, 19 years of age, with his father (postcard photo prior to 1937). Courtesy of Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Robert_Wadlow_postcard.jpg).
